patência do canal arterial no recém-nascido de pré-termo
TRANSCRIPT
2019/2020
Joana Cristina Gouveia Santos
Patência do canal arterial no recém-nascido de pré-termo:
experiência de um hospital terciário
abril, 2020
Mestrado Integrado em Medicina
Área: Medicina clínica
Tipologia: Dissertação
Trabalho efetuado sob a Orientação de:
Professora Doutora Hercília Guimarães
Trabalho organizado de acordo com as normas da revista:
Revista Portuguesa de Cardiologia.
Joana Cristina Gouveia Santos
Patência do canal arterial no recém-nascido de pré-termo:
experiência de um hospital terciário
abril, 2020
UC Dissertação/Projeto (6º Ano) - DECLARAÇÃO DE INTEGRIDADE
Eu, Joana Cristina Gouveia Santos, abaixo assinado, nº mecanográfico 200203685, estudante do 6º
ano do Ciclo de Estudos Integrado em Medicina, na Faculdade de Medicina da Universidade do Porto,
declaro ter atuado com absoluta integridade na elaboração deste projeto de opção.
Neste sentido, confirmo que NÃO incorri em plágio (ato pelo qual um indivíduo, mesmo por omissão,
assume a autoria de um determinado trabalho intelectual, ou partes dele). Mais declaro que todas as
frases que retirei de trabalhos anteriores pertencentes a outros autores, foram referenciadas, ou
redigidas com novas palavras, tendo colocado, neste caso, a citação da fonte bibliográfica.
Faculdade de Medicina da Universidade do Porto, 17/04/2020
Assinatura conforme cartão de identificação:
________________________________________________
UC Dissertação/Projeto (6º Ano) – DECLARAÇÃO DE REPRODUÇÃO
NOME
Joana Cristina Gouveia Santos
NÚMERO DE ESTUDANTE E-MAIL
200203685 [email protected] DESIGNAÇÃO DA ÁREA DO PROJECTO
Medicina clínica
TÍTULO DISSERTAÇÃO/MONOGRAFIA (riscar o que não interessa)
Patência do canal arterial no recém-nascido de pré-termo: experiência de um hospital terciário
ORIENTADOR
Professora Doutora Hercília Guimarães
COORIENTADOR (se aplicável)
ASSINALE APENAS UMA DAS OPÇÕES:
É AUTORIZADA A REPRODUÇÃO INTEGRAL DESTE TRABALHO APENAS PARA EFEITOS DE INVESTIGAÇÃO, MEDIANTE DECLARAÇÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE.
É AUTORIZADA A REPRODUÇÃO PARCIAL DESTE TRABALHO (INDICAR, CASO TAL SEJA NECESSÁRIO, Nº MÁXIMO DE PÁGINAS, ILUSTRAÇÕES, GRÁFICOS, ETC.) APENAS PARA EFEITOS DE INVESTIGAÇÃO, MEDIANTE DECLARAÇÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE.
DE ACORDO COM A LEGISLAÇÃO EM VIGOR, (INDICAR, CASO TAL SEJA NECESSÁRIO, Nº MÁXIMO DE PÁGINAS, ILUSTRAÇÕES, GRÁFICOS, ETC.) NÃO É PERMITIDA A REPRODUÇÃO DE QUALQUER PARTE DESTE TRABALHO.
Faculdade de Medicina da Universidade do Porto, 17/04/2020
Assinatura conforme cartão de identificação: ______________________________________________
iii
Índice
Abreviaturas iv
Resumo 1
Abstract 2
Introdução 3
Métodos 6
Resultados 8
Discussão 10
Conclusão 14
Referências 15
Figuras
Figura 1
Figura 2
19
20
Tabelas
Tabela 1
Tabela 2
Tabela 3
21
23
24
Anexo I – Normas da Revista portuguesa de cardiologia
v
iv
Abreviaturas
CA Canal arterial
CHUSJ Centro Hospitalar Universitário de São João
COX Enzima ciclooxigenase
CPAP Ventilação com pressão positiva contínua das vias aéreas
DBP Displasia broncopulmonar
DMH Doença das membranas hialinas
EVPV enfarte venoso periventricular
FO forâmen ovale
HIV hemorragia intraventricular
IG Idade gestacional
NEC Enterocolite necrosante
PCA Patência do canal arterial
PCA-HS Patência do canal arterial hemodinâmicamente significativa
RNPT Recém-nascidos de pré-termo
ROP Retinopatia da prematuridade
RVP Resistência vascular pulmonar
TORCH Acrónimo de toxoplasmose, outras (sífilis, vírus varicela-zoster,
parvovírus B19), rubéola, citomegalovírus, e vírus herpes simples.
VAFO Ventilação de alta frequência oscilatória
VM Ventilação mecânica
1
Patência do canal arterial no recém-nascido de pré-termo: experiência de um
hospital terciário
Joana Santos1, Paulo Soares1,2, Cristina Ferreras1,3, Filipa Flor-de-Lima1,2
Hercília Guimarães1,4
1 Faculdade de Medicina da Universidade do Porto, Portugal
2 Serviço de Neonatologia, Centro Hospitalar Universitário de São João, Porto, Portugal
3 Serviço de Pediatria, Centro Hospitalar Universitário de São João, Porto, Portugal
4 Cardiovascular R&D Center, Faculty of Medicine University of Porto, Portugal
Resumo
Introdução: A patência do canal arterial (PCA) nos recém-nascidos de pré-termo (RNPT)
tem vindo a ser associada ao aumento de mortalidade e de co-morbilidades. Este estudo
objetivou caracterizar a população de RNPT diagnosticados com PCA e identificar
fatores preditivos de resposta ao tratamento médico do mesmo.
Métodos: Foi realizado um estudo observacional retrospetivo de oito anos, que incluiu
todos os RNPT com idade gestacional compreendida entre as 23 e as 32 semanas com
diagnóstico de PCA, admitidos no Serviço de Neonatologia do Centro Hospitalar
Universitário de São João (CHUSJ). Realizou-se análise comparativa univariada, e
foram explorados os modelos preditivos da eficácia do tratamento de PCA com
ibuprofeno, por análise de regressão logística multivariável.
Resultados: Cumpriram critérios de inclusão no estudo 115 casos e foram excluídos 34,
obtendo-se a amostra final de 81 RNPT com PCA. A análise univariável revelou
diferenças significativas na eficácia de encerramento pelo tratamento médico com
ibuprofeno em diversas variáveis, e obteve-se um modelo de regressão logístico
multivariado (capacidade discriminativa 72,2%, sensibilidade 98,1%, especificidade
57,1%), considerando o efeito das variáveis: idade gestacional, tipo de parto,
necessidade de tratamento com diuréticos e de transfusão de plaquetas.
Conclusão: Este estudo permitiu caraterizar a população de RNPT com diagnóstico de
PCA e a identificação de um modelo preditivo que poderá auxiliar na previsão da eficácia
de resposta ao tratamento médico e deste modo contribuir para otimizar a estratégia de
abordagem aos não respondedores ao tratamento médico.
Palavras chave: Recém-nascido pré-termo, patência do canal arterial, ibuprofeno
2
Patent ductus arteriosus in preterm newborns: experience at a tertiary hospital
Joana Santos1, Paulo Soares1,2, Cristina Ferreras1,3, Filipa Flor-de-Lima1,2
Hercília Guimarães1,4
1 Faculdade de Medicina da Universidade do Porto, Portugal
2 Serviço de Neonatologia, Centro Hospitalar Universitário de São João, Porto, Portugal
3 Serviço de Pediatria, Centro Hospitalar Universitário de São João, Porto, Portugal
4 Cardiovascular R&D Center, Faculty of Medicine University of Porto, Portugal
Abstract
Introduction: Patent ductus arteriosus (PDA) in preterm newborns has been associated
with increased mortality and co-morbidities. This study aimed to characterize the
population of preterm infants diagnosed with PDA and to identify predictive factors of
response to medical treatment of PDA.
Methods: An eight-year retrospective observational study was carried out, which
included all PTNBs with gestational age between 23 and 32 weeks diagnosed with PDA,
admitted to the HSJ Obstetrics Service. Univariate comparative analysis was performed,
and models for predicting the effectiveness of PDA treatment with ibuprofen were
explored by multivariate logistic regression analysis.
Results: Were included in the study 115 cases and 34 were excluded, with a final sample
of 81 PTNB with PDA. The univariable analysis revealed significant differences in the
closure efficacy by medical treatment with ibuprofen in several variables, and a
multivariate logistic regression model was obtained (discriminative capacity 72.2%,
sensitivity 98.1%, specificity 57.1%), considering the effect of gestational age, type of
delivery, need for diuretics treatment and platelet transfusion.
Conclusion: This study allowed to characterize the population of preterm infants
diagnosed with PDA and the identification of a predictive model that can aid to predict
the effectiveness to the medical treatment and thus contribute to optimize the medical
approach to the non-responders.
Keywords: preterm newborns, patent ductus arteriosus, ibuprofen
3
Introdução
A transição para a vida extrauterina representa uma fase crítica de adaptação fisiológica
com impacto significativo em diversos órgãos e sistemas, particularmente no pulmão e
coração. A maioria dos neonatos completam esta fase de transição sem complicações,
no entanto a desregulação da normal adaptação pós-natal pode conduzir a instabilidade
cardiopulmonar, com necessidade de cuidados intensivos avançados, principalmente
em recém-nascidos prematuros.1,2
No feto existem dois shunts, o forâmen ovale (FO) da aurícula direita para a esquerda,
e o canal arterial (CA) da artéria pulmonar para a aorta. Quase todo o débito cardíaco
direito, não oxigenado, circula através do CA para a aorta descendente onde é
transportado pela aorta e artérias umbilicais até à placenta. Dada a baixa tensão de
oxigénio fetal é mantida a vasoconstrição pulmonar com alta resistência pulmonar o que
promove o shunt direito-esquerdo através do FO e CA.1
Nas primeiras 48-72 horas após o nascimento ocorre a diminuição progressiva da
resistência vascular pulmonar (RVP) em resposta ao recrutamento e aumento da
concentração de oxigénio alveolar. Á medida que a RVP decresce, a direção do fluxo
através do CA e FO passa para um padrão bidirecional ou direção esquerda-direita
exclusiva, o que promove a circulação pulmonar.1 O aumento da saturação arterial de
oxigénio, a produção de bradicinina endotelial e a diminuição dos níveis de
prostaglandinas E2 placentária em circulação, induzem a constrição do CA, seguido do
seu encerramento fisiológico.3 Deste modo, em cerca de 96% dos recém-nascidos
saudáveis de termo o encerramento funcional do CA ocorre até às 48h de vida, podendo
permanecer nos restantes casos um pequeno canal com fluxo esquerdo-direito
restritivo.4 Por outro lado, a patência de canal arterial (PCA) é a alteração cardiovascular
mais frequente em recém-nascidos de pré-termo (RNPT), sendo inversamente
proporcional à idade gestacional (IG) e ao peso ao nascimento.5 Deste modo, a PCA
ocorre em cerca de 33% dos prematuros de muito baixo peso (igual ou inferior a 1500
gramas), e em cerca de 65% dos prematuros de extremo baixo peso (igual ou inferior a
1000 gramas).6,7 Estimando-se uma frequência de PCA de cerca de 20% em prematuros
de 32 semanas de IG, enquanto que em prematuros de extremo baixo peso com IG
igual ou inferior a 26 semanas a frequência ronda os 80-90%.8 A presença de
mediadores inflamatórios sistémicos condiciona um aumento de espécies reativas de
oxigénio, assim como de prostaglandinas, que poderão contribuir para a falência do
encerramento espontâneo do CA. Adicionalmente, outros aspetos que poderão
contribuir para a PCA em RNPT são o aumento da sensibilidade das células musculares
lisas aos efeitos das substâncias vasodilatadoras,9 a insufiência da glândula supra-
renal,10 a trombocitopenia,11-13 e a disfunção plaquetária.14 Por outro lado, fatores
4
relativos à ressuscitação e cuidados pós-natais em RNPT tais como a exposição a
ventilação com pressão positiva, a concentração de oxigénio, e o recurso a surfactante
exógeno, poderão também contribuir para a PCA.3
A importância clínica da PCA relaciona-se com as suas dimensões, a magnitude do
shunt e da consequente repercussão cardiovascular e respiratória resultantes do
hiperfluxo pulmonar, sobrecarga cardíaca e hipoperfusão sistémica.15 O quadro clínico
de PCA hemodinâmicamente significativa (PCA-HS) inclui sinais respiratórios
(necessidade crescente de oxigénio, dependência de ventilação e apneias), e sinais
hemodinâmicos (sopro sistólico ou contínuo, precórdio hiperdinâmico, pulsos amplos,
hipotensão diastólica, cardiomegalia, hepatomegalia ou acidose metabólica).16 A PCA-
HS no RNPT tem vindo a ser associada ao aumento de mortalidade e de co-
morbilidades.5 Os RNPT com PCA apresentam frequentemente várias outras
complicações da prematuridade, tais como a hemorragia pulmonar, a hemorragia
peri/intraventricular (HIV), a enterocolite necrosante (NEC), a displasia broncopulmonar
(DBP) e a leucomalácia periventricular,5 estando contudo, ainda por esclarecer se estas
complicações surgem num quadro geral relacionado com a imaturidade do RNPT ou se
existe uma relação com a PCA.
O diagnóstico de PCA com significado hemodinâmico deve ser precoce e assenta num
conjunto de vários parâmetros ecográficos. Esta avaliação ecocardiográfica deve ser
realizada nas primeiras 72 horas nos recém-nascidos com idade gestacional igual ou
inferior a 28 semanas e/ou peso ao nascer igual ou inferior a 1000 gramas; ou recém-
nascidos com idade gestacional entre as 28 e 30 semanas com fatores de risco
associados (ausência de corticoterapia pré-natal, sepsis, ventilação invasiva, asfixia
peri-parto, e mãe sob terapêutica com sulfato de magnésio). Em todos os restantes
RNPT a avaliação ecocardiográfica deve ser realizada se existir quadro clínico
sugestivo.16
O tratamento médico para o encerramento precoce da PCA, tem o intuito de evitar as
repercussões clínicas e deve ser iniciado nos primeiros 5 dias de vida com um ciclo de
ibuprofeno (3 doses 10 mg/kg/dia por perfusão endovenosa de 15 minutos).16 A eficácia
de encerramento de PCA após o primeiro ciclo de tratamento com ibuprofeno é de
70%.17 No caso de falência de resposta está indicado um segundo ciclo de tratamento,
podendo ser ponderado um terceiro ciclo em casos excecionais.16 O encerramento
cirúrgico da PCA está indicado apenas nos casos de falência do tratamento
farmacológico, ou na presença de outras co-morbilidades que contraindicam o
tratamento farmacológico: insuficiência renal, trombocitopenia, hemorragia ativa ou
alterações da coagulação, enterocolite necrosante, sepsis grave, hipertensão pulmonar,
hiperbilirrrubinemia e perfuração intestinal. A abordagem cirúrgica é bastante eficaz e
globalmente segura. Contudo existem riscos de perturbação grave hemodinâmica com
5
alguns casos descritos de falência cardiovascular potencialmente grave no pós-
operatório imediato. Todavia as complicações mais frequentemente associadas à
laqueação cirúrgica de PCA incluem hemorragia, hipotensão arterial, disfunção cardíaca
aguda, lesão dos nervos recorrente ou frénico, derrame pleural, pneumotórax e
quilotórax.17
Neste estudo pretendeu-se caracterizar a população de RNPT diagnosticados com
PCA, e identificar fatores preditivos de resposta ao tratamento médico, contribuindo
assim para uma melhor compreensão desta condição e das co-morbilidades mais
frequentemente associadas e permitindo uma melhor estratificação da prestação de
cuidados a RNPT com PCA-HS.
6
Métodos
População em estudo
Foi realizado um estudo observacional retrospetivo tendo sido incluídos todos os RNPT
com idade gestacional entre as 23 e as 32 semanas (23 semanas e 0 dias e 31 semanas
e 6 dias), determinada por ecografia até às 20 semanas, e admitidos no Serviço de
Neonatologia procedentes do Serviço de Obstetrícia/bloco de partos do Centro
Hospitalar São João (CHUSJ), entre janeiro de 2010 e dezembro de 2018, com
diagnóstico de PCA. Os critérios de exclusão foram: (1) RNPT nascido noutra instituição
e submetido a transporte neonatal para o Serviço de Neonatologia do CHUSJ; (2) RNPT
com diagnóstico adicional de: a) infeção do grupo TORCH; b) anomalia congénita major;
c) cromossomopatia: d) asfixia (índice de Apgar aos 5 minutos menor ou igual a 5 ou pH
do sangue do cordão umbilical inferior a 7,0); e) síndrome de transfusão feto-fetal; f)
discrepância de crescimento fetal (diferença superior a 20% em relação ao peso do
maior feto); g) anemia severa na admissão (hemoglobina inferior a 12 g/dl); h)
diagnóstico de erro inato do metabolismo efetuado em consulta pré-natal ou durante o
período neonatal; i) suspeita ou diagnóstico de doença neuromuscular.
Dados clínicos e demográficos
Os dados relativos à história pré-natal, do nascimento e reanimação na sala de partos,
co-morbilidades e tratamentos efetuados foram recolhidos através da consulta da base
de dados clínicos. De modo a garantir a confidencialidade dos dados foi atribuído um
código a cada processo dos doentes incluídos no estudo, do conhecimento exclusivo do
investigador. Este estudo obteve parecer e aprovação favorável da Comissão de Ética
e autorização do Conselho de Administração e Responsável pelo Acesso à informação
do Centro Hospitalar de São João.
Análise estatística
A avaliação da normalidade foi testada com recurso ao teste de Kolmogorov-smirnov.
As variáveis categóricas foram descritas em número total e percentagem, as variáveis
contínuas de distribuição normal foram descritas pela média e desvio padrão (σ), e as
variáveis contínuas de distribuição não normal descritas pela mediana, valor mínimo e
máximo. Foi estudada a análise comparativa univariada utilizando os testes de X2 para
variáveis categóricas, o teste T de student para variáveis contínuas de distribuição
normal e o teste Wilcoxon-Mann-Whitney para as variáveis contínuas de distribuição
não normal. Foi utilizada regressão logística multivariável (método forward) para
explorar modelos preditivos da eficácia do tratamento médico de PCA com ibuprofeno,
a partir das associações encontradas pela análise univariável (p<0.25). Foi considerado
7
nível de significância de alfa de 0.05. A análise estatística foi realizada com o software
SPSS 26.0 ® (IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp.).
8
Resultados
Análise descritiva da população em estudo
Entre janeiro de 2010 e dezembro de 2018, registaram-se 115 diagnósticos de PCA em
RNPT com IG compreendida entre as 23 e as 32 semanas, admitidos no Serviço de
Neonatologia do Centro Hospitalar Universitário de São João. Destes, foram excluídos
34 RNPT: 29 nascidos noutra instituição e submetidos a transporte neonatal para o
Serviço de Neonatologia do CHUSJ, dois por diagnóstico de anomalia congénita major,
dois por asfixia (índice de Apgar aos 5 minutos inferior a 5) e um por infeção do grupo
TORCH. As caraterísticas da população de 81 recém-nascidos pré-termo incluídos no
estudo estão representadas na Tabela 1 e os dados de diagnóstico, abordagem e
tratamento de patência do canal arterial representados na Figura 1.
Análise univariada
A análise univariável entre a eficácia de encerramento pelo tratamento médico com
ibuprofeno e as diversas variáveis estudadas revelou diferenças significativas para o
tipo de parto (eutócico ou cesariana); para a idade gestacional, a média do peso, o
comprimento, o perímetro cefálico, a média da hemoglobina e o volume globular ao
nascimento; para o número de dias de utilização de CPAP nasal e em nutrição
parentérica total; para a necessidade e número de transfusão de glóbulos vermelhos e
plaquetas; para a necessidade de ventilação mecânica (VM) invasiva durante o
internamento; para a necessidade de tratamento com corticoides e broncodilatadores
inalados e diuréticos; para a necessidade de oxigénio suplementar na alta; e para o
diagnóstico de retinopatia da prematuridade (ROP), HIV e de enfarte venoso
periventricular (EVPV) associado a HIV (Tabela 3).
Regressão logística binominal
A regressão logística multivariável (método forward) explorou modelos preditivos da
eficácia do tratamento médico de PCA com ibuprofeno, a partir das associações
encontradas pela análise univariável (p<0,25). O modelo de regressão logístico que
considerou o efeito das variáveis: idade gestacional, tipo de parto, necessidade de
tratamento com diuréticos e de transfusão de plaquetas foi estatisticamente significativo,
χ2(4) = 35,947, p < 0,0001. O modelo explica 64,3% (Nagelkerke R2) da variância da
eficácia do tratamento médico de PCA com ibuprofeno e classifica corretamente 89,7%
dos casos. A sensibilidade do modelo foi de 98,1%, a especificidade de 57,1%, e obteve-
se um valor preditivo positivo de 89,8%, e um valor preditivo negativo de 88,8%. A
capacidade discriminativa do modelo dada pela área sob a curva ROC foi 0,782
9
(Intervalo de Confiança a 95%, 0,624 - 0,941) o que é um nível de discriminação
aceitável de acordo com o teste de Hosmer e Lemeshow (Figura 2).18
10
Discussão
A sobrevivência dos RNPT tem vindo a aumentar significativamente ao longo das
últimas duas décadas.19 Devendo-se este facto à identificação precoce das patologias
específicas dos RNPT e na sua melhoria assistencial. Uma das entidades cujo
diagnóstico e tratamento precoce tem vindo a melhorar a sobrevida dos RNPT é a PCA.
Permanece, no entanto, por esclarecer se as diversas co-morbilidades identificadas
surgem como resultado da prematuridade, da existência de PCA com significado
hemodinâmico ou com as intervenções terapêuticas. Adicionalmente, o tempo ideal para
a intervenção terapêutica após o diagnóstico de PCA continua incerto, uma vez que
aguardar pelo encerramento espontâneo poderá prevenir o sobretratamento e os efeitos
adversos associados e o próprio tratamento com ibuprofeno parece ser efetivo mesmo
quando aplicado relativamente mais tarde.7 Todavia, tem vindo a ser recomentado o
tratamento agressivo e precoce da PCA de modo a prevenir outras complicações. O
conhecimento e caracterização das diferentes variáveis, entre as quais da história pré-
natal, do nascimento e reanimação na sala de partos, de outras co-morbilidades e dos
tratamentos efetuados, poderá permitir a estratificação dos RNPT com PCA e deste
modo melhorar a intervenção e o outcome destes prematuros.
Na prática clínica, nem todos os RNPT com diagnóstico de PCA respondem ao
tratamento com inibidores da enzima ciclooxigenase (COX). Lago e colaboradores,
observaram uma resposta eficaz ao tratamento com ibuprofeno em 86% dos indivíduos
incluídos no estudo.20 Deste modo, torna-se fundamental determinar os fatores
preditores do sucesso terapêutico para o encerramento de PCA com ibuprofeno de
modo a melhorar a abordagem individual a este grupo de prematuros, evitando assim a
exposição desnecessária a fármacos e eventualmente considerar a abordagem
cirúrgica mais precocemente no algoritmo de decisão. Observou-se o encerramento
eficaz do CA após o tratamento com ibuprofeno em 80,6% dos RNPT incluídos no
estudo. Porém ao final do 1º ciclo de tratamento com ibuprofeno a eficácia de
encerramento foi de 62,5%. Os valores encontrados, são ligeiramente inferiores à
eficácia de encerramento descrita quer global quer ao final do 1º ciclo de tratamento
(86% e 73%, respetivamente),17 o que poderá estar relacionado com o intervalo de idade
gestacional mais baixos incluídos neste estudo (até às 31 semanas e 6 dias).
Adicionalmente, neste estudo observou-se superioridade na eficácia de encerramento
de PCA pelo tratamento com ibuprofeno para IG, peso, comprimento e perímetro
cefálico ao nascimento superiores. Outros estudos relacionaram a eficácia do
tratamento com inibidores da COX com a maturação do CA, tendo sido demonstrada
que o peso ao nascimento e IG inferiores estão associados ao maior diâmetro ductal,
dificultando deste modo o encerramento farmacológico.21-23
11
Os nossos dados sugerem que o parto por cesariana poderá promover uma melhor
resposta e eficácia ao tratamento com ibuprofeno. Esta observação é apoiada por
alguns estudos que estimaram efeitos protetores do parto por cesariana particularmente
em RNPT com muito baixo peso, quando comparados com o parto vaginal
espontâneo.24 No entanto são necessários estudos prospetivos em larga escala de
modo a estabelecer essa associação.
Foi proposto por alguns autores que as plaquetas desempenham um papel importante
no encerramento do canal arterial fisiológico após a constrição funcional inicial do CA.25
No presente estudo, nos RNPT que necessitaram de transfusão de plaquetas a eficácia
de encerramento com o tratamento com ibuprofeno foi de apenas 50% e o número
médio de transfusões de plaquetas foi superior no grupo em que este tratamento não
foi eficaz. Estudos anteriores, descreveram contagens iniciais de plaquetas mais altas
nos RNPT que responderam eficazmente ao tratamento com indometacina em
comparação aos que não responderam.26 Por outro lado, Akar e colaboradores
observaram que a massa plaquetária não afeta a eficácia do tratamento com ibuprofeno
para PCA em prematuros.27 Os dados do presente estudo sugerem que a necessidade
de transfusões de plaquetas estará associada a pior resposta ao tratamento com
ibuprofeno, contudo serão necessários mais estudos que esclareçam esta relação. Não
obstante, no subgrupo de RNPT que necessitaram de transfusões de plaquetas (n=20;
IG entre as 23 e 29 semanas e peso compreendido entre 410 e 1110 gramas), seis
necessitaram de laqueação cirúrgica e nove vieram a falecer, o que corrobora o pior
prognóstico deste subgrupo de prematuros. No entanto, salienta-se a relação da
contagem de plaquetas e a necessidade de transfusão com outros fatores, tais como a
infeção, que podem contribuir para o pior prognóstico e mortalidade neste subgrupo.
A doença das membranas hialinas (DMH) não só aumenta a incidência de PCA em
RNPT como também foi associado à eficácia de resposta ao tratamento de PCA com
inibidores da COX.28 Adicionalmente, a administração de surfactante provoca uma
rápida diminuição da resistência vascular pulmonar, contribuindo para o aumento de
fluxo esquerdo-direito através do canal arterial.29 No entanto, no presente estudo
observou-se a presença de DMH em 90,1% da amostra, tendo sido utilizado surfactante
em 84% dos RNPT incluídos no estudo, o que dificulta a atribuição de uma associação
para estas variáveis.
A DBP é definida como a dependência de oxigénio às 36 semanas de IG, e apresenta
uma incidência superior quanto menor o peso dos recém-nascidos ao nascimento.30 A
patogénese da DBP é multifatorial e associada a alguns fatores de risco da
prematuridade.30 No período pós-natal, diversas medidas na abordagem do RNPT têm
sido utilizadas de modo a prevenir e tratar a DBP. Recorre-se ao uso de diuréticos de
12
ansa, tais como a furosemida, para melhorar a função pulmonar e diminuir a resistência
vascular pulmonar.31 Contudo, o uso de furosemida tem vindo a ser associado a
diversos efeitos colaterais, entre os quais a inibição da resposta ao tratamento com
inibidores da COX.32 Na nossa amostra verificou-se também que o tratamento com
diuréticos foi estatisticamente associado à redução da eficácia de encerramento de PCA
após o tratamento. Adicionalmente, os broncodilatadores e os corticoides inalados que
são também utilizados na melhoria nas trocas gasosas e na mecânica pulmonar na
prevenção da DBP,33 foram associados a uma resposta menos eficaz ao tratamento
com ibuprofeno no presente estudo. Por outro lado, vários estudos associam a presença
de PCA com o desenvolvimento de DBP34, destacando a necessidade de ser
esclarecida a relação entre estas variáveis.
Adicionalmente a utilização de ventilação mecânica ao nascimento foi associado ao
aumento de risco de PCA com significado hemodinâmico.35 A necessidade de ventilação
mecânica mais agressiva poderá assim relacionar a existência de PCA e o aumento de
risco de displasia broncopulmonar em RNPT. Por outro lado, o encerramento
farmacológico de PCA está associado com a diminuição do edema pulmonar e logo com
a diminuição de DBP e necessidade de ventilação.36 Os resultados obtidos neste estudo
associam a menor eficácia de encerramento de PCA com a necessidade de ventilação
mecânica invasiva.
Neste estudo, observamos associação de eficácia do tratamento com ibuprofeno com
os valores de hemoglobina e de volume globular ao nascimento. Salientando-se que
todos os RNPT que não necessitaram de transfusão de glóbulos vermelhos durante o
internamento (n=20) responderam ao tratamento com ibuprofeno. Sabe-se que a
transfusão de hemácias melhora a condição cardio-respiratória pelo aumento de
hemoglobina em circulação e consequente melhoria da oxigenação tecidual. No
entanto, alguns estudos, associam a transfusão de hemácias a resultados clínicos
adversos em RNPT, tais como a NEC, a DBP, a HIV e a ROP.38
Na série em estudo, excecionalmente, foi utilizado paracetamol para o tratamento da
PCA em três RNPT. Estudos recentes sobre a utilização deste fármaco no encerramento
de PCA têm demonstrado que este é igualmente seguro e eficaz quando comparado
com os tratamentos com ibuprofeno ou indometacina, apresentando poucos efeitos
adversos.39 Deste modo, poderá ser uma solução segura em situações que
contraindicam o uso de ibuprofeno.40 Contudo, vários estudos estão atualmente em
curso de modo a averiguar a possibilidade da utilização de paracetamol de modo mais
alargado, uma vez que alguns estudos sugerem a sua associação com lesões pré-renais
e complicações relacionadas com o neurodesenvolvimento.39
No caso de falência de resposta ao tratamento médico após o segundo ciclo, poderá
ser ponderado em casos excecionais a realização de um terceiro ciclo.16 Na nossa série
13
este foi realizado em cinco RNPT tendo sido eficaz em todos. Esta amostra compreendia
RNPT de IG entre as 24 e 31 semanas, com peso ao nascimento entre 685 e 1925
gramas. Estes resultados salientam a importância do censo clínico na tomada de
decisão do algoritmo de tratamento de PDA.
O encerramento cirúrgico de PCA reduz o tempo em ventilação mecânica, melhora a
resposta hemodinâmica e a compliance pulmonar. Contudo, não está isento de efeitos
adversos e por isso reservado para os casos em que ocorre falência do tratamento
médico.40 Na nossa amostra, em 13 casos foi necessário realizar a laqueação cirúrgica
do canal arterial, tendo ocorrido diversas complicações pós-cirúrgicas, enfatizando
deste modo a necessidade de definir o subgrupo de RNPT com PCA-HS nos quais a
cirurgia tem maior probabilidade de ser benéfica.
Este estudo apresenta as desvantagens associadas ao facto de ser um estudo
retrospetivo e como tal haver um controlo limitado das variáveis da amostra e de
existirem processos de dados clínicos incompletos, contudo foi possível obter uma
amostra robusta para a análise pretendida. Apresenta ainda a limitação de ter sido
realizado apenas num único centro, no entanto com a vantagem de se tratar de um
centro de nível III e centro de referência de cardiopatias congénitas o que permite a
garantia de assistência diferenciada e integrada dos RNPT, garantindo a acessibilidade,
eficácia, segurança e excelência dos cuidados prestados obedecendo aos mais
elevados padrões éticos e científicos internacionais.
14
Conclusão
A patência do canal arterial é uma condição frequentemente observada em RNPT e a
sua abordagem terapêutica continua a ser um desafio. O encerramento da PCA, por
tratamento médico ou cirúrgico não é isento de complicações e a decisão continua
controversa. Os inibidores da cicloxigenase (COX), tais como o ibuprofeno, são
frequentemente utilizados para o tratamento de PCA em RNPT. No entanto, observa-se
na prática clínica que nem todos os RNPT com PCA respondem ao tratamento com
ibuprofeno. Alguns estudos têm demonstrado que algumas variáveis tais como a IG, o
peso ao nascimento e o diâmetro do canal poderão auxiliar a prever a resposta
terapêutica aos inibidores da COX. Neste estudo, procuramos caraterizar a população
de RNPT com diagnóstico de PCA e descrever os fatores que poderão prever o sucesso
terapêutico do uso de ibuprofeno no encerramento de PCA. Segundo o modelo de
regressão logístico multivariado que considera o efeito das variáveis idade gestacional,
tipo de parto, necessidade de tratamento com diuréticos e de transfusão de plaquetas é
possível prever com elevada sensibilidade a eficácia de resposta ao tratamento médico.
Contudo, mais estudos serão necessários com o intuito de melhorar este modelo, no
sentido de otimizar as estratégias terapêuticas a oferecer aos RNPT com diagnóstico
de PCA.
15
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19
Figura 1 – Abordagem terapêutica e resultados obtidos nos recém-nascidos de pré-
termo com patência do canal arterial incluídos no estudo. Legenda: RNPT: recém-
nascidos de pré-termo; PCA: patência do canal arterial; CHUSJ: Centro Hospitalar
Universitário de São João; TORCH acrónimo de: Toxoplasmose, Outras (sífilis, vírus
varicela-zoster (VVZ), parvovírus B19), Rubéola, Citomegalovírus (CMV), e vírus herpes
simples (HSV).
20
Figura 2 - Capacidade discriminativa do modelo preditivo da ocorrência de eficácia do
tratamento com ibuprofeno no encerramento do canal arterial (área sob a curva ROC =
0,782; intervalo de confiança a 95% 0,624 a 0,941) em recém-nascidos de pré-termo
com idade gestacional entre as 23 e 32 semanas.
21
Tabela 1 - Caraterísticas da população de recém-nascidos pré-termo incluídos no
estudo.
Dados dos recém-nascidos ao nascimento
Peso (gramas) [média (desvio padrão)] 995,84 (301,25)
Comprimento (centímetros) [mediana (mínimo-máximo)] 34,5 (25,0-52,0)
Perímetro cefálico (centímetros) [mediana (mínimo-máximo)] 25,5 (15,0-33,0)
Idade Gestacional (semanas) [mediana (mínimo-máximo)] 27 (23-32)
Idade materna (anos) [mediana (mínimo-máximo)] 33 (19-47)
Sexo masculino [nº (%)] 38 (46,9)
Hemoglobina (grama/decilitro) [média (desvio padrão)] 16,2 (2,6)
Volume globular (%) [média (desvio padrão)] 45,9 (7,1)
Leucócitos (x 109/litro) [mediana (mínimo-máximo)] 7,3 (2,6-53,2)
Neutrófilos (%) [média (desvio padrão)] 33,5 (17,4)
Linfócitos (%) [média (desvio padrão)] 52,2 (19,0)
Contagem de plaquetas [média (desvio padrão)] 185873 (48635)
Fatores Pré-natais
Primigesta [nº (%)] 46 (56,8)
Gestação espontânea [nº (%)] 70 (86,4)
Gestação vigiada [nº (%)] 77 (95,0)
Gestação única [nº (%)] 52 (64,2)
Corticoterapia antenatal [nº (%)] 70 (86,4)
Ciclo completo de corticoterapia [nº (%)] 55 (78,6)
Sulfato de magnésio (protocolo neuroprotector) [nº (%)] 11 (13,6)
Ciclo completo [nº (%)] 10 (91,0)
Parto por cesariana [nº (%)] 56 (69,1)
Rutura prematura de membranas (superior a 18 horas) [nº (%)] 9 (11,1)
Corioamnionite clínica [nº (%)] 6 (7,4)
Incompetência cervical [nº (%)] 10 (12,4)
Descolamento prematuro de placenta normalmente inserida [nº (%)] 12 (14,8)
Grávida com hipertensão arterial crónica [nº (%)] 3 (3,7)
Pré-eclâmpsia [nº (%)] 19 (23,5)
Eclâmpsia [nº (%)] 1 (1,2)
Síndrome HELLP [nº (%)] 4 (5,0)
Hipertensão arterial gestacional [nº (%)] 1 (1,2)
Diabetes tipo I [nº (%)] 1 (1,2)
Diabetes gestacional [nº (%)] 5 (6,2)
Necessidade de insulina na gestação [nº (%)] 0 (0,0)
Tabagismo na gestação [nº (%)] 6 (7,4)
Restrição de crescimento fetal [nº (%)] 6 (7,4)
Ação na Sala de Partos
Ventilação Mecânica [nº (%)] 67 (82,7)
Ventilação mecânica invasiva com tubo endotraqueal [nº (%)] 35 (43,2)
Ventilação com pressão positiva contínua das vias aéreas (CPAP) nasal [nº (%)] 47 (58,0)
Oxigénio suplementar [nº (%)] 76 (93,8)
Fração inspirada de oxigénio (FiO2) máximo [mediana (mínimo-máximo)] 0,3 (0,0-1,0)
Índice de Apgar ao 1º minuto [mediana (mínimo-máximo)] 6 (2-9)
Índice de Apgar ao 5º minuto [mediana (mínimo-máximo)] 8 (4-10)
Período pós-natal
Displasia broncopulmonaren [nº (%)] 28 (34,6)
Doença das membranas hialinas [nº (%)] 73 (90,1)
Ligeira [nº (%)] 31 (42,5)
Moderada [nº (%)] 31 (42,5)
Grave [nº (%)] 11 (15,1)
Utilização de surfactante [nº (%)] 68 (84,0)
Uma dose [nº (%)] 28 (41,2)
Duas doses [nº (%)] 25 (36,8)
Três doses [nº (%)] 13 (19,1)
Quatro doses [nº (%)] 2 (2,9)
Pneumotórax [nº (%)] 11 (13,6)
22
Atelectasia pulmonar [nº (%)] 6 (7,4)
Utilização de Ventilação mecânica [nº (%)] 78 (96,3)
Duração de utilização de ventilação mecânica (dias) [média (desvio padrão)] 38,5 (23,3)
Utilização de pressão positiva contínua das vias aéreas (CPAP) nasal [nº (%)] 69 (85,2)
Duração de utilização de CPAP nasal (dias) [média (desvio padrão)] 25,8 (18,6)
Utilização de ventilação mecânica (VM) invasiva [nº (%)] 65 (80,2)
Duração de utilização de VM invasiva [mediana (mínimo-máximo)] 8 (1-73)
Utilização de ventilação de alta frequência oscilatória (VAFO) [nº (%)] 9 (11,1)
Duração de utilização de VAFO [mediana (mínimo-máximo)] 8 (3-23)
Fração inspirada de oxigénio máximo no internamento [mediana (mínimo-máximo)] 0,4 (0,21-1,0)
Número de dias com oxigénio suplementar [mediana (mínimo-máximo)] 35 (0-157)
Necessidade de oxigénio suplementar na alta [nº (%)] 28 (34,6)
Tratamento com corticóide sistémico [nº (%)] 10 (12,3)
Tratamento com corticóide inalado [nº (%)] 18 (22,2)
Tratamento com broncodilatador inalado [nº (%)] 19 (23,5)
Tratamento com diuréticos [nº (%)] 9 (11,1)
Dias de nutrição parentérica total [mediana (mínimo-máximo)] 3 (0-206)
Necessidade de transfusão de glóbulos vermelhos [nº (%)] 58 (71,6)
Necessidade de transfusão de plaquetas [nº (%)] 20 (24,7)
Enterocolite necrosante [nº (%)] 5 (6,2)
Sépsis precoce (inferior a 72h de vida) [nº (%)] 2 (2,5)
Sépsis hospitalar (superior a 72h de vida) [nº (%)] 33 (40,7)
Pneumonia [nº (%)] 12 (14,8)
Meningite [nº (%)] 2 (2,5)
Hemorragia intraventricular [nº (%)] 39 (48,1)
Enfarte venoso periventricular associado a hemorragia intraventricular [nº (%)] 10 (25,6)
Leucomalácia periventricular [nº (%)] 51 (63,0)
Grau 1 [nº (%)] 44 (86,2)
Grau 2 [nº (%)] 6 (11,8)
Grau 3 [nº (%)] 1 (2,0)
Retinopatia da prematuridade [nº (%)] a 43 (53,1)
Grau I [nº (%)] 27 (62,8)
Grau II [nº (%)] 9 (21,0)
Grau III [nº (%)] 7 (16,3)
Cirurgia por retinopatia da prematuridade [nº (%)] 13 (30,2)
Óbito [nº (%)] 15 (18,5)
Óbitos com idade gestacional inferior a 36 semanas [nº (%)] 14 (93,3)
Óbitos com idade gestacional superior a 36 semanas [nº (%)] 1 (6,7)
Idade no óbito [mediana (mínimo-máximo)] 11,5 (6-96)
Dados na alta
Duração do internamento (dias) [média (desvio padrão)] 58,44 (37,8)
Peso (gramas) [mediana (mínimo-máximo)] 2175 (485-3420)
Comprimento (centímetros) [mediana (mínimo-máximo)] 43 (30-50)
Perímetro cefálico (centímetros) [mediana (mínimo-máximo)] 32 (22,5-38) a a avaliação de ROP é desconhecida em 7 dos casos incluídos no estudo.
23
Tabela 2 - Diagnóstico, abordagem e tratamento de patência do canal arterial.
Diagnóstico e tratamento de patência do canal arterial
Recém-nascidos pré-termo com diagnóstico de patência do canal arterial 81
Dia de diagnóstico de patência do canal arterial [mediana (mínimo-máximo)] 3 (1-50)
Tratamento de patência do canal arterial com ibuprofeno [nº (%)] [nº (%)]
73 (90,1)
Um ciclo [nº (%)] 46 (63,0)
Dois ciclos [nº (%)] 22 (30,1)
Três ciclos [nº (%)] 5 (6,8)
Dia de início de tratamento com ibuprofeno [mediana (mínimo-máximo)] 3 (1-31)
Encerramento eficaz após o tratamento com ibuprofeno [nº (%)] 58 (80,6)
Tratamento de patência do canal arterial com paracetamol [nº (%)] 3 (3,7)
Encerramento cirúrgico [nº (%)] 13 (16,0)
Dia de vida do encerramento cirúrgico [mediana (mínimo-máximo)] 14 (7-50)
Complicações pós-cirurgia [nº (%)] 2 (15,4)
24
Tabela 3 – Análise univariável entre a eficácia de encerramento pelo tratamento médico
com ibuprofeno e as diversas variáveis estudadas.
Tratamento eficaz
Tratamento não eficaz
Valor p
Idade gestacional [média (desvio padrão)] 28,0 (1,9) 26,1 (2,4) 0,000
Idade gestacional inferior a 28 semanas [nº (%)] 24 (42,1) 13 (86,7) 0,002
Idade gestacional igual ou superior 28 semanas [nº (%)] 33 (57,9) 2 (13,3)
Tipo de parto - Eutócico [nº (%)] 13 (22,8) 8 (53,3) 0,021
- Cesariana [nº (%)] 44 (77,2) 7 (46,7)
Peso ao nascimento (gramas) [média (desvio padrão)] 1069,3 (290,5) 752,4 (216,6) 0,000
Comprimento (centímetros) [média (desvio padrão)] 35,8 (4,2) 32,3 (4,5) 0,000
Perímetro cefálico (centímetros) [média (desvio padrão)] 26,1 (2,3) 23,9 (3,6) 0,000
Hemoglobina (grama/decilitro) [média (desvio padrão)] 16,8 (2,7) 14,3 (1,6) 0,000
Volume globular (%) [média (desvio padrão)] 47,3 (7,5) 41,5 (3,9) 0,003
Transfusão de Glóbulos Vermelhos (não) [nº (%)] 20 (35,1) 0 (0,0) 0,007
(sim) 37 (64,9) 15 (100,0)
Transfusão de plaquetas (não) [nº (%)] 48 (84,2) 6 (40) 0,000
(sim) 9 (15,8) 9 (60)
Número de transfusões de eritrócitos [média (desvio padrão)] 2,4 (3,6) 8,6 (8,0) 0,000
Número de transfusões de plaquetas [média (desvio padrão)] 0,35 (1,2) 3,4 (7,4) 0,002
Ventilação mecânica (não) [nº (%)] 12 (21,1) 0 (0,0) 0,046
(sim) 45 (78,9) 15 (100)
Duração de utilização de CPAP nasal [média (desvio padrão)] 29,5 (16,0) 21,6 (23,7) 0,034
Necessidade de oxigénio na alta (sim) [nº (%)] 43 (75,4) 7 (46,7) 0,031
Dias de nutrição parentérica [média (desvio padrão)] 3,1 (3,5) 24,4 (49,9) 0,001
Tratamento com corticóide inalado (não) [nº (%)] 46 (80,7) 8 (53,3) 0,029
(sim) 11 (19,3) 7 (46,7)
Tratamento com broncodilatador inalado (não) [nº (%)] 45 (78,8) 8 (53,3) 0,045
(sim) 12 (21,1) 7 (46,7)
Tratamento com diurético (não) [nº (%)] 54 (94,7) 9 (60,0) 0,000
(sim) 3 (5,3) 6 (40,0)
Hemorragia intraventricular (não) [nº (%)] 35 (61,4) 4 (26,7) 0,016
(sim) 22 (38,6) 11 (73,3)
EVPV associado a HIV (não) [nº (%)] 55 (96,5) 12 (80,0) 0,025
(sim) 2 (3,5) 3 (20,0)
Retinopatia da prematuridade (não) [nº (%)] 21 (38,2) 2 (14,3) 0,002
(sim) 33 (60,0) 8 (57,1) CPAP - ventilação com pressão positiva contínua das vias aéreas; EVPV - enfarte venoso periventricular; HIV - hemorragia intraventricular
v
Anexo I - Normas da revista de cardiologia portuguesa
Revista Portuguesa de Cardiologia
AUTHORS INFORMATION PACK
GUIDE FOR AUTHORS
INTRODUCTIONThe Portuguese Journal of Cardiology, the official journal of the Portuguese Society ofCardiology, was founded in 1982 with the aim of keeping Portuguese cardiologists informedthrough the publication of scientific articles on areas such as arrhythmology andelectrophysiology, cardiovascular surgery, intensive care, coronary artery disease,cardiovascular imaging, hypertension, heart failure and cardiovascular prevention.The Journal isa monthly publication with high standards of quality in terms of scientific content andproduction. Since 1999 it has been published in English as well as Portuguese, which haswidened its readership abroad.
The Journal accepts the following categories of articles:
Research (Original Investigation and Meta-Analysis), Review and Education (NarrativeReviews, Systematic Reviews -without meta-analysis, Guidelines, Case Reports, Images inCardiology and Snapshots), Opinion (Current Perspective), Correspondence (EditorialComment, Letters to the Editor, Research Letter and Observation)
Types of articleManuscripts submitted for publication should be prepared in accordance with the"Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work inMedical Journals" of the International Committee of Medical Journal Editors (ICMJE). Thisdocument is available at http://www.icmje.org/recommendations/.
Summary table of Revista Portuguesa de Cardiologia types of article characteristics.
Original Investigation
Original Investigation articles cover areas of clinical or basic research: Clinical trial, Meta-analysis, Intervention study, Cohort study, Case-control study, Epidemiologicassessment, Survey with high response rate, Cost-effectiveness analysis, Decisionanalysis, Study of screening and diagnostic tests, Other observational studies) . They shouldhave a maximum of 5000 words, with a total of up to 15 tables and/or figures, and should bestructured as follows: Abstract (maximum 250 words; divided into Introduction and Objectives,Methods, Results and Conclusion(s)); 3-10 keywords; Introduction; Objectives; Methods; Results;Discussion; Conclusion(s); Acknowledgements, if any; References (up to 75); and figure legends,if any. Follow EQUATOR Reporting Guidelines.
Review Articles and Systematic Reviews
Review Articles should have a maximum of 5000 words, with a total of up to 15 tables and/or
figures, and should be structured as follows: Abstract (maximum 250 words; unstructured); 3-10keywords; Introduction; thematic sections at the discretion of the authors; Conclusion(s);Acknowledgements, if any; References (up to 100); and figure legends, if any.
Systematic Reviews should be structured as Introduction, Methods, Results, Discussion andConclusion(s). The subject should be clearly defined. The objective of a systematic reviewshould be to produce an evidence-based conclusion. The Methods should give a clear indicationof the literature search strategy, data extraction, grading of evidence and analysis.
Systematic Reviews should not normally exceed 4000 words, with a total of up to 6 tablesand/or figures and up to 100 references.
Au tho rs a re s t rong ly recommended to consu l t the PR ISMA s ta tement(http://www.prisma-statement.org/), which is intended to help improve the reporting ofsystematic reviews and meta-analyses. We encourage authors to develop a systematic reviewprotocol (e.g. following PRISMA-P) and register with PROSPERO.
Guidelines
It is recommended to consult the AGREE II instrument for which items should be reported thathighlighted particular quality aspects of guideline development. In general, publishedstatements intended to guide clinical care (e.g., guidelines, practice parameters,recommendations, consensus statements and position papers) should describe the clinicalproblem to be addressed, the mechanism by which the statement was generated, a review ofthe evidence for the statement (if available), and the statement on practice itself.
To minimize confusion and to enhance transparency, such statements should begin with thefollowing questions, followed by brief comments addressing each question:
What other guideline statements are available on this topic?Why was this guideline developed?How does this statement differ from existing guidelines?Why does this statement differ from existing guidelines?
The statement should have an unstructured abstract of up to 350 words, 3 to 10 keywords andcan include up to 4000 words, a total of up to 6 tables and/or figures and up to 100 references.
Case Reports
Authors should use the CARE guidelines as a guiding framework. Case reports should notexceed 1500 words of body text, with up to 15 references and four tables or figures. They mustinclude an abstract (unstructured, maximum 250 words) and bulleted statements (maximum 70words) in answer to the following questions: What’s already known about this topic? and Whatdoes this study add?Please see the Ethics section of the Instructions regarding preservation of patients’privacy. Case Reports must have no more than 5 authors.
Images in Cardiology
Images in Cardiology should have a maximum of 250 words, without Abstract, keywords, tables,or division into sections and up to 5 references may be included.
Snapshots
This section is intended for the publication of rare or educational cases or novel techniques incardiology. The text should not exceed 500 words and up to 3 figures with brief captions and upto 5 references may be included. Snapshots must have no more than 3 authors.
Current Perspective
This type of manuscript is submitted upon invitation by the Editorial Board. It may cover a broaddiversity of themes focusing on cardiology and healthcare: current or emerging problems,management and health policies, history of medicine, society issues and epidemiology, amongothers. An author who wishes to propose a manuscript in this section is requested to send anabstract to the Editor-in-Chief including the title and Author list for evaluation. The text shouldnot exceed 1200 words, and up to 10 references, two tables or two figures are allowed. Anabstract is not required.
Editorial Comment
Editorials are submitted at the invitation of the Editor. They should not exceed 1500 words andcan contain up to 20 references and 1 table and 1 figure. They do not have an Abstract orkeywords.
Letters to the Editor
Letters to the Editor on articles previously published in the Journal will be considered up to 8weeks after the publication of the article in question. They should not exceed 800 words andcan contain up to 2 figures but without Abstract, keywords or tables. They should have no morethan 3 authors.
Research Letter
Research Letters are concise, focused reports of original research. These should not exceed 600words of text and 6 references and may include up to 2 tables or figures. Online supplementarymaterial is not allowed. Research Letters may have no more than 7 authors.
Observation
Observations consisting of short reports of 1 or 2 complicated, unique cases should not exceed600 words of text (not including acknowledgment, tables, figures, acknowledgments, andreferences) and 6 references and may include up to 2 tables or figures. Online supplementarymaterial is not allowed. Observations may have no more than 7 authors.
If the patient(s) described in these manuscripts is identifiable, a Patient Permission form mustbe completed and signed by the patient(s) and submitted with the manuscript. Omitting data ormaking data less specific to deidentify patients is acceptable but changing any such data is notacceptable.
Contact details for submissionYou can send your manuscript at https://www.editorialmanager.com/repc
LanguageThis journal is published in Portuguese and in English language.The title (and abstract and key words if applicable) must be submitted in both English andPortuguese.
Articles submitted to the Journal should be clearly written in Portuguese (from Portugal) and/orEnglish of a good standard. Text may be edited to maintain linguistic quality and to conformwith standard American English.
Submission checklistYou can use this list to carry out a final check of your submission before you send it to thejournal for review. Please check the relevant section in this Guide for Authors for more details.Ensure that the following items are present:One author has been designated as the corresponding author with contact details:• E-mail address• Full postal addressAll necessary files have been uploaded:Manuscript:• Include keywords• All figures (include relevant captions)• All tables (including titles, description, footnotes)• Ensure all figure and table citations in the text match the files provided• Indicate clearly if color should be used for any figures in printGraphical Abstracts / Highlights files (where applicable)Supplemental files (where applicable)Further considerations• Manuscript has been 'spell checked' and 'grammar checked'• All references mentioned in the Reference List are cited in the text, and vice versa• Permission has been obtained for use of copyrighted material from other sources(including the Internet)• A competing interests statement is provided, even if the authors have no competing intereststo declare• Journal policies detailed in this guide have been reviewed• Referee suggestions and contact details provided, based on journal requirements
For further information, visit our Support Center.
BEFORE YOU BEGIN
Ethics in publishingPlease see our information pages on Ethics in publishing and Ethical guidelines for journalpublication.
Studies in humans and animalsIf the work involves the use of human subjects, the author should ensure that the workdescribed has been carried out in accordance with The Code of Ethics of the World MedicalAssociation (Declaration of Helsinki) for experiments involving humans. The manuscript shouldbe in line with the Recommendations for the Conduct, Reporting, Editing and Publication ofScholarly Work in Medical Journals and aim for the inclusion of representative humanpopulations (sex, age and ethnicity) as per those recommendations. The terms sex andgender should be used correctly.
The privacy rights of human subjects must always be observed. A statement must be includedto the effect that the study was conducted in accordance with the amended Declaration ofHelsinki, that the local institutional review board or independent ethics committee approved the
protocol, and that written informed consent was obtained from all patients. The name of thecommittee, the name of the chairperson of the committee (or the person who approved theprotocol), the date of approval and the approval number should follow this statement in theMethods section. For multicenter studies, a list of the relevant approvals may be provided in aseparate document to be published as supplementary material.
All animal experiments should comply with the ARRIVE guidelines and should be carried out inaccordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associatedguidelines, EU Directive 2010/63/EU for animal experiments, or the National Institutes of Healthguide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978) andthe authors should clearly indicate in the manuscript that such guidelines have been followed.The sex of animals must be indicated, and where appropriate, the influence (or association) ofsex on the results of the study.
Conflicts of Interest and Financial DisclosuresAll authors must disclose any financial and personal relationships with other people ororganizations that could inappropriately influence (bias) their work. Examples of potentialcompeting interests include employment, consultancies, stock ownership, honoraria, paidexpert testimony, patent applications/registrations, and grants or other funding. A conflict ofinterest may exist when an author (or the author's institution or employer) has financial orpersonal relationships or affiliations that could influence (or bias) the author's decisions, work,or manuscript. All authors are required to report potential conflicts of interest including specificfinancial interests relevant to the subject of their manuscript.
Authors must disclose any interests in two places: 1. A summary declaration of intereststatement in the title page file (if double-blind) or the manuscript file (if single-blind). If thereare no interests to declare then please state this: 'Declarations of interest: none'. This summarystatement will be ultimately published if the article is accepted. 2. Detailed disclosures as partof a separate Declaration of Interest form, which forms part of the journal's official records. It isimportant for potential interests to be declared in both places and that the informationmatches. More information.
Submission declaration and verificationSubmission of an article implies that the work described has not been published previously(except in the form of an abstract or as part of a published lecture or academic thesis, see'Multiple, redundant or concurrent publication' section of our ethics policy for more information),that it is not under consideration for publication elsewhere, that its publication is approved byall authors and tacitly or explicitly by the responsible authorities where the work was carriedout, and that, if accepted, it will not be published elsewhere in the same form, in English or inany other language, including electronically without the written consent of the copyright-holder.To verify originality, your article may be checked by the originality detection service CrossrefSimilarity Check.
AuthorshipEach author should have participated sufficiently in the work to take public responsibility forappropriate portions of the content. One or more authors should take responsibility for theintegrity of the work as a whole, from inception to published article. According to the guidelinesof the International Committee of Medical Journal Editors (ICMJE), authorship credit should bebased on the following 4 criteria:1. substantial contributions to conception or design of the work, or the acquisition, analysis, or
interpretation of data for the work; and2. drafting of the work or revising it critically for important intellectual content; and3. final approval of the version to be published; and4. agreement to be accountable for all aspects of the work in ensuring that questions related tothe accuracy or integrity of any part of the work are appropriately investigated and resolved.
Changes to authorship. Role of the corresponding authorA single corresponding author (or coauthor designee in the event that the corresponding authoris unavailable) will serve on behalf of all coauthors as the primary correspondent with theeditorial office during the submission and review process. If the manuscript is accepted, thecorresponding author will review an edited manuscript and proof, make decisions regardingrelease of information in the manuscript to the news media or federal agencies, handle allpostpublication communications and inquiries, and will be identified as the correspondingauthor in the published article. The corresponding author also is responsible for ensuring thatthe Acknowledgment section of the manuscript is complete and that the conflict of interestdisclosures reported of the manuscript are accurate, up-to-date, and consistent with theinformation provided in each author's potential conflicts of interest section in the AuthorshipForm.
Authors are expected to consider carefully the list and order of authors before submitting theirmanuscript and provide the definitive list of authors at the time of the original submission. Anyaddition, deletion or rearrangement of author names in the authorship list should be made onlybefore the manuscript has been accepted and only if approved by the journal Editor. Torequest such a change, the Editor must receive the following from the corresponding author:(a) the reason for the change in author list and (b) written confirmation (e-mail, letter) from allauthors that they agree with the addition, removal or rearrangement. In the case of addition orremoval of authors, this includes confirmation from the author being added or removed.Only in exceptional circumstances will the Editor consider the addition, deletion orrearrangement of authors after the manuscript has been accepted. While the Editor considersthe request, publication of the manuscript will be suspended. If the manuscript has alreadybeen published in an online issue, any requests approved by the Editor will result in acorrigendum.
Clinical trial resultsIn line with the position of the International Committee of Medical Journal Editors, the journalwill not consider results posted in the same clinical trials registry in which primary registrationresides to be prior publication if the results posted are presented in the form of a briefstructured (less than 500 words) abstract or table. However, divulging results in othercircumstances (e.g., investors' meetings) is discouraged and may jeopardise consideration ofthe manuscript. Authors should fully disclose all posting in registries of results of the same orclosely related work.
Reporting clinical trialsThe ICMJE defines a clinical trial as any research project that prospectively assigns humanparticipants to intervention or comparison groups to study the cause-and-effect relationshipbetween an intervention and a health outcome. Interventions include but are not limited todrugs, surgical procedures, devices, behavioral treatments, educational programs, dietaryinterventions, quality improvement interventions, process-of-care changes, and the like.
All manuscripts reporting clinical trials, including those limited to secondary exploratory or post
hoc analysis of trial outcomes, must include the following:· · CONSORT flow diagram· Completed trial checklist· Registry at an appropriate online public clinical trial registry· A Data Sharing Statement to indicate if data will be shared or not. Specific questions regardingthe sharing of data are included in the manuscript submission system.
Trial RegistrationIn concert with the ICMJE, our journal requires, as a condition of consideration for publication,registration of all trials in a public trials registry that is acceptable to the ICMJE (ie, the registrymust be owned by a not-for-profit entity, be publicly accessible, and require the minimumregistration data set as described by ICMJE).Acceptable trial registries include the following and others listed at http://www.icmje.org:
anzctr.org.auclinicaltrials.govisrctn.orgtrialregister.nlumin.ac.jp/ctr
CopyrightUpon acceptance of an article, authors will be asked to complete a 'Journal PublishingAgreement' (see more information on this). An e-mail will be sent to the corresponding authorconfirming receipt of the manuscript together with a 'Journal Publishing Agreement' form or alink to the online version of this agreement.
Author rightsAs an author you (or your employer or institution) have certain rights to reuse your work. Moreinformation.
Elsevier supports responsible sharingFind out how you can share your research published in Elsevier journals.
Role of the funding sourceYou are requested to identify who provided financial support for the conduct of the researchand/or preparation of the article and to briefly describe the role of the sponsor(s), if any, instudy design; in the collection, analysis and interpretation of data; in the writing of the report;and in the decision to submit the article for publication. If the funding source(s) had no suchinvolvement then this should be stated.
Open accessThis is an open access journal: all articles will be immediately and permanently free foreveryone to read and download. To provide open access, this journal has an open access fee(also known as an article publishing charge APC) which needs to be paid by the authors or ontheir behalf e.g. by their research funder or institution. Permitted third party (re)use is definedby the following Creative Commons user licenses:
Open AccessPlease visit our Open Access page from the Journal Homepage for more information.
Elsevier Researcher AcademyResearcher Academy is a free e-learning platform designed to support early and mid-careerresearchers throughout their research journey. The "Learn" environment at ResearcherAcademy offers several interactive modules, webinars, downloadable guides and resources toguide you through the process of writing for research and going through peer review. Feel freeto use these free resources to improve your submission and navigate the publication processwith ease.
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Patient Identification
Omitting data or making data less specific to deidentify patients is acceptable, but changingany such data is not acceptable. Only those details essential for understanding and interpretinga specific case report or case series should be provided. Although the degree of specificityneeded will depend on the context of what is being reported, specific ages, race/ethnicity, andother sociodemographic details should be presented only if clinically or scientifically relevantand important. Cropping of photographs to remove identifiable personal features that are notessential to the clinical message may be permitted as long as the photographs are nototherwise altered. Please do not submit masked photographs of patients. Patients' initials orother personal identifiers must not appear in an image.
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for final publication. All correspondence, including notification of the Editor's decision andrequests for revision, is sent by e-mail.
Submit your articlePlease submit your article via https://www.editorialmanager.com/repc
RefereesPlease submit the names and institutional e-mail addresses of several potential referees. Formore details, visit our Support site. Note that the editor retains the sole right to decide whetheror not the suggested reviewers are used.
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Peer reviewers will respond to the Editor within 30 days recommending acceptance, revision orrejection. The Editor will decide within 10 days whether to accept the manuscript withoutmodification, to send the reviewers’ comments to the authors for modification, or to reject it.When modifications are proposed, the authors have 30 days (which can be extended onrequest) to submit a revised version of the manuscript, incorporating the comments of thereviewers and the Editor. Any amendments should be highlighted in a different colour. TheEditor will decide within 10 days whether to accept the new version, reject it, or send it forfurther review by one or more reviewers.
Letters to the Editor and Editorials will be reviewed by the Editorial Board, but external peerreview may also be requested.
Use of word processing softwareIt is important that the file be saved in the native format of the word processor used. The textshould be in single-column format. Keep the layout of the text as simple as possible. Mostformatting codes will be removed and replaced on processing the article. In particular, do notuse the word processor's options to justify text or to hyphenate words. However, do use boldface, italics, subscripts, superscripts etc. When preparing tables, if you are using a table grid,use only one grid for each individual table and not a grid for each row. If no grid is used, usetabs, not spaces, to align columns. The electronic text should be prepared in a way very similarto that of conventional manuscripts (see also the Guide to Publishing with Elsevier). Note thatsource files of figures, tables and text graphics will be required whether or not you embed yourfigures in the text. See also the section on Electronic artwork.To avoid unnecessary errors you are strongly advised to use the 'spell-check' and 'grammar-check' functions of your word processor.
Article structure
Revista Portuguesa de Cardiologia
AUTHORS INFORMATION PACK
GUIDE FOR AUTHORS
INTRODUCTIONThe Portuguese Journal of Cardiology, the official journal of the Portuguese Society ofCardiology, was founded in 1982 with the aim of keeping Portuguese cardiologists informedthrough the publication of scientific articles on areas such as arrhythmology andelectrophysiology, cardiovascular surgery, intensive care, coronary artery disease,cardiovascular imaging, hypertension, heart failure and cardiovascular prevention.The Journal isa monthly publication with high standards of quality in terms of scientific content andproduction. Since 1999 it has been published in English as well as Portuguese, which haswidened its readership abroad.
The Journal accepts the following categories of articles:
Research (Original Investigation and Meta-Analysis), Review and Education (NarrativeReviews, Systematic Reviews -without meta-analysis, Guidelines, Case Reports, Images inCardiology and Snapshots), Opinion (Current Perspective), Correspondence (EditorialComment, Letters to the Editor, Research Letter and Observation)
Types of articleManuscripts submitted for publication should be prepared in accordance with the"Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work inMedical Journals" of the International Committee of Medical Journal Editors (ICMJE). Thisdocument is available at http://www.icmje.org/recommendations/.
Summary table of Revista Portuguesa de Cardiologia types of article characteristics.
Original Investigation
Original Investigation articles cover areas of clinical or basic research: Clinical trial, Meta-analysis, Intervention study, Cohort study, Case-control study, Epidemiologicassessment, Survey with high response rate, Cost-effectiveness analysis, Decisionanalysis, Study of screening and diagnostic tests, Other observational studies) . They shouldhave a maximum of 5000 words, with a total of up to 15 tables and/or figures, and should bestructured as follows: Abstract (maximum 250 words; divided into Introduction and Objectives,Methods, Results and Conclusion(s)); 3-10 keywords; Introduction; Objectives; Methods; Results;Discussion; Conclusion(s); Acknowledgements, if any; References (up to 75); and figure legends,if any. Follow EQUATOR Reporting Guidelines.
Review Articles and Systematic Reviews
Review Articles should have a maximum of 5000 words, with a total of up to 15 tables and/or
figures, and should be structured as follows: Abstract (maximum 250 words; unstructured); 3-10keywords; Introduction; thematic sections at the discretion of the authors; Conclusion(s);Acknowledgements, if any; References (up to 100); and figure legends, if any.
Systematic Reviews should be structured as Introduction, Methods, Results, Discussion andConclusion(s). The subject should be clearly defined. The objective of a systematic reviewshould be to produce an evidence-based conclusion. The Methods should give a clear indicationof the literature search strategy, data extraction, grading of evidence and analysis.
Systematic Reviews should not normally exceed 4000 words, with a total of up to 6 tablesand/or figures and up to 100 references.
Au tho rs a re s t rong ly recommended to consu l t the PR ISMA s ta tement(http://www.prisma-statement.org/), which is intended to help improve the reporting ofsystematic reviews and meta-analyses. We encourage authors to develop a systematic reviewprotocol (e.g. following PRISMA-P) and register with PROSPERO.
Guidelines
It is recommended to consult the AGREE II instrument for which items should be reported thathighlighted particular quality aspects of guideline development. In general, publishedstatements intended to guide clinical care (e.g., guidelines, practice parameters,recommendations, consensus statements and position papers) should describe the clinicalproblem to be addressed, the mechanism by which the statement was generated, a review ofthe evidence for the statement (if available), and the statement on practice itself.
To minimize confusion and to enhance transparency, such statements should begin with thefollowing questions, followed by brief comments addressing each question:
What other guideline statements are available on this topic?Why was this guideline developed?How does this statement differ from existing guidelines?Why does this statement differ from existing guidelines?
The statement should have an unstructured abstract of up to 350 words, 3 to 10 keywords andcan include up to 4000 words, a total of up to 6 tables and/or figures and up to 100 references.
Case Reports
Authors should use the CARE guidelines as a guiding framework. Case reports should notexceed 1500 words of body text, with up to 15 references and four tables or figures. They mustinclude an abstract (unstructured, maximum 250 words) and bulleted statements (maximum 70words) in answer to the following questions: What’s already known about this topic? and Whatdoes this study add?Please see the Ethics section of the Instructions regarding preservation of patients’privacy. Case Reports must have no more than 5 authors.
Images in Cardiology
Images in Cardiology should have a maximum of 250 words, without Abstract, keywords, tables,or division into sections and up to 5 references may be included.
Snapshots
This section is intended for the publication of rare or educational cases or novel techniques incardiology. The text should not exceed 500 words and up to 3 figures with brief captions and upto 5 references may be included. Snapshots must have no more than 3 authors.
Current Perspective
This type of manuscript is submitted upon invitation by the Editorial Board. It may cover a broaddiversity of themes focusing on cardiology and healthcare: current or emerging problems,management and health policies, history of medicine, society issues and epidemiology, amongothers. An author who wishes to propose a manuscript in this section is requested to send anabstract to the Editor-in-Chief including the title and Author list for evaluation. The text shouldnot exceed 1200 words, and up to 10 references, two tables or two figures are allowed. Anabstract is not required.
Editorial Comment
Editorials are submitted at the invitation of the Editor. They should not exceed 1500 words andcan contain up to 20 references and 1 table and 1 figure. They do not have an Abstract orkeywords.
Letters to the Editor
Letters to the Editor on articles previously published in the Journal will be considered up to 8weeks after the publication of the article in question. They should not exceed 800 words andcan contain up to 2 figures but without Abstract, keywords or tables. They should have no morethan 3 authors.
Research Letter
Research Letters are concise, focused reports of original research. These should not exceed 600words of text and 6 references and may include up to 2 tables or figures. Online supplementarymaterial is not allowed. Research Letters may have no more than 7 authors.
Observation
Observations consisting of short reports of 1 or 2 complicated, unique cases should not exceed600 words of text (not including acknowledgment, tables, figures, acknowledgments, andreferences) and 6 references and may include up to 2 tables or figures. Online supplementarymaterial is not allowed. Observations may have no more than 7 authors.
If the patient(s) described in these manuscripts is identifiable, a Patient Permission form mustbe completed and signed by the patient(s) and submitted with the manuscript. Omitting data ormaking data less specific to deidentify patients is acceptable but changing any such data is notacceptable.
Contact details for submissionYou can send your manuscript at https://www.editorialmanager.com/repc
LanguageThis journal is published in Portuguese and in English language.The title (and abstract and key words if applicable) must be submitted in both English andPortuguese.
Articles submitted to the Journal should be clearly written in Portuguese (from Portugal) and/orEnglish of a good standard. Text may be edited to maintain linguistic quality and to conformwith standard American English.
Submission checklistYou can use this list to carry out a final check of your submission before you send it to thejournal for review. Please check the relevant section in this Guide for Authors for more details.Ensure that the following items are present:One author has been designated as the corresponding author with contact details:• E-mail address• Full postal addressAll necessary files have been uploaded:Manuscript:• Include keywords• All figures (include relevant captions)• All tables (including titles, description, footnotes)• Ensure all figure and table citations in the text match the files provided• Indicate clearly if color should be used for any figures in printGraphical Abstracts / Highlights files (where applicable)Supplemental files (where applicable)Further considerations• Manuscript has been 'spell checked' and 'grammar checked'• All references mentioned in the Reference List are cited in the text, and vice versa• Permission has been obtained for use of copyrighted material from other sources(including the Internet)• A competing interests statement is provided, even if the authors have no competing intereststo declare• Journal policies detailed in this guide have been reviewed• Referee suggestions and contact details provided, based on journal requirements
For further information, visit our Support Center.
BEFORE YOU BEGIN
Ethics in publishingPlease see our information pages on Ethics in publishing and Ethical guidelines for journalpublication.
Studies in humans and animalsIf the work involves the use of human subjects, the author should ensure that the workdescribed has been carried out in accordance with The Code of Ethics of the World MedicalAssociation (Declaration of Helsinki) for experiments involving humans. The manuscript shouldbe in line with the Recommendations for the Conduct, Reporting, Editing and Publication ofScholarly Work in Medical Journals and aim for the inclusion of representative humanpopulations (sex, age and ethnicity) as per those recommendations. The terms sex andgender should be used correctly.
The privacy rights of human subjects must always be observed. A statement must be includedto the effect that the study was conducted in accordance with the amended Declaration ofHelsinki, that the local institutional review board or independent ethics committee approved the
protocol, and that written informed consent was obtained from all patients. The name of thecommittee, the name of the chairperson of the committee (or the person who approved theprotocol), the date of approval and the approval number should follow this statement in theMethods section. For multicenter studies, a list of the relevant approvals may be provided in aseparate document to be published as supplementary material.
All animal experiments should comply with the ARRIVE guidelines and should be carried out inaccordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associatedguidelines, EU Directive 2010/63/EU for animal experiments, or the National Institutes of Healthguide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978) andthe authors should clearly indicate in the manuscript that such guidelines have been followed.The sex of animals must be indicated, and where appropriate, the influence (or association) ofsex on the results of the study.
Conflicts of Interest and Financial DisclosuresAll authors must disclose any financial and personal relationships with other people ororganizations that could inappropriately influence (bias) their work. Examples of potentialcompeting interests include employment, consultancies, stock ownership, honoraria, paidexpert testimony, patent applications/registrations, and grants or other funding. A conflict ofinterest may exist when an author (or the author's institution or employer) has financial orpersonal relationships or affiliations that could influence (or bias) the author's decisions, work,or manuscript. All authors are required to report potential conflicts of interest including specificfinancial interests relevant to the subject of their manuscript.
Authors must disclose any interests in two places: 1. A summary declaration of intereststatement in the title page file (if double-blind) or the manuscript file (if single-blind). If thereare no interests to declare then please state this: 'Declarations of interest: none'. This summarystatement will be ultimately published if the article is accepted. 2. Detailed disclosures as partof a separate Declaration of Interest form, which forms part of the journal's official records. It isimportant for potential interests to be declared in both places and that the informationmatches. More information.
Submission declaration and verificationSubmission of an article implies that the work described has not been published previously(except in the form of an abstract or as part of a published lecture or academic thesis, see'Multiple, redundant or concurrent publication' section of our ethics policy for more information),that it is not under consideration for publication elsewhere, that its publication is approved byall authors and tacitly or explicitly by the responsible authorities where the work was carriedout, and that, if accepted, it will not be published elsewhere in the same form, in English or inany other language, including electronically without the written consent of the copyright-holder.To verify originality, your article may be checked by the originality detection service CrossrefSimilarity Check.
AuthorshipEach author should have participated sufficiently in the work to take public responsibility forappropriate portions of the content. One or more authors should take responsibility for theintegrity of the work as a whole, from inception to published article. According to the guidelinesof the International Committee of Medical Journal Editors (ICMJE), authorship credit should bebased on the following 4 criteria:1. substantial contributions to conception or design of the work, or the acquisition, analysis, or
interpretation of data for the work; and2. drafting of the work or revising it critically for important intellectual content; and3. final approval of the version to be published; and4. agreement to be accountable for all aspects of the work in ensuring that questions related tothe accuracy or integrity of any part of the work are appropriately investigated and resolved.
Changes to authorship. Role of the corresponding authorA single corresponding author (or coauthor designee in the event that the corresponding authoris unavailable) will serve on behalf of all coauthors as the primary correspondent with theeditorial office during the submission and review process. If the manuscript is accepted, thecorresponding author will review an edited manuscript and proof, make decisions regardingrelease of information in the manuscript to the news media or federal agencies, handle allpostpublication communications and inquiries, and will be identified as the correspondingauthor in the published article. The corresponding author also is responsible for ensuring thatthe Acknowledgment section of the manuscript is complete and that the conflict of interestdisclosures reported of the manuscript are accurate, up-to-date, and consistent with theinformation provided in each author's potential conflicts of interest section in the AuthorshipForm.
Authors are expected to consider carefully the list and order of authors before submitting theirmanuscript and provide the definitive list of authors at the time of the original submission. Anyaddition, deletion or rearrangement of author names in the authorship list should be made onlybefore the manuscript has been accepted and only if approved by the journal Editor. Torequest such a change, the Editor must receive the following from the corresponding author:(a) the reason for the change in author list and (b) written confirmation (e-mail, letter) from allauthors that they agree with the addition, removal or rearrangement. In the case of addition orremoval of authors, this includes confirmation from the author being added or removed.Only in exceptional circumstances will the Editor consider the addition, deletion orrearrangement of authors after the manuscript has been accepted. While the Editor considersthe request, publication of the manuscript will be suspended. If the manuscript has alreadybeen published in an online issue, any requests approved by the Editor will result in acorrigendum.
Clinical trial resultsIn line with the position of the International Committee of Medical Journal Editors, the journalwill not consider results posted in the same clinical trials registry in which primary registrationresides to be prior publication if the results posted are presented in the form of a briefstructured (less than 500 words) abstract or table. However, divulging results in othercircumstances (e.g., investors' meetings) is discouraged and may jeopardise consideration ofthe manuscript. Authors should fully disclose all posting in registries of results of the same orclosely related work.
Reporting clinical trialsThe ICMJE defines a clinical trial as any research project that prospectively assigns humanparticipants to intervention or comparison groups to study the cause-and-effect relationshipbetween an intervention and a health outcome. Interventions include but are not limited todrugs, surgical procedures, devices, behavioral treatments, educational programs, dietaryinterventions, quality improvement interventions, process-of-care changes, and the like.
All manuscripts reporting clinical trials, including those limited to secondary exploratory or post
hoc analysis of trial outcomes, must include the following:· · CONSORT flow diagram· Completed trial checklist· Registry at an appropriate online public clinical trial registry· A Data Sharing Statement to indicate if data will be shared or not. Specific questions regardingthe sharing of data are included in the manuscript submission system.
Trial RegistrationIn concert with the ICMJE, our journal requires, as a condition of consideration for publication,registration of all trials in a public trials registry that is acceptable to the ICMJE (ie, the registrymust be owned by a not-for-profit entity, be publicly accessible, and require the minimumregistration data set as described by ICMJE).Acceptable trial registries include the following and others listed at http://www.icmje.org:
anzctr.org.auclinicaltrials.govisrctn.orgtrialregister.nlumin.ac.jp/ctr
CopyrightUpon acceptance of an article, authors will be asked to complete a 'Journal PublishingAgreement' (see more information on this). An e-mail will be sent to the corresponding authorconfirming receipt of the manuscript together with a 'Journal Publishing Agreement' form or alink to the online version of this agreement.
Author rightsAs an author you (or your employer or institution) have certain rights to reuse your work. Moreinformation.
Elsevier supports responsible sharingFind out how you can share your research published in Elsevier journals.
Role of the funding sourceYou are requested to identify who provided financial support for the conduct of the researchand/or preparation of the article and to briefly describe the role of the sponsor(s), if any, instudy design; in the collection, analysis and interpretation of data; in the writing of the report;and in the decision to submit the article for publication. If the funding source(s) had no suchinvolvement then this should be stated.
Open accessThis is an open access journal: all articles will be immediately and permanently free foreveryone to read and download. To provide open access, this journal has an open access fee(also known as an article publishing charge APC) which needs to be paid by the authors or ontheir behalf e.g. by their research funder or institution. Permitted third party (re)use is definedby the following Creative Commons user licenses:
Open AccessPlease visit our Open Access page from the Journal Homepage for more information.
Elsevier Researcher AcademyResearcher Academy is a free e-learning platform designed to support early and mid-careerresearchers throughout their research journey. The "Learn" environment at ResearcherAcademy offers several interactive modules, webinars, downloadable guides and resources toguide you through the process of writing for research and going through peer review. Feel freeto use these free resources to improve your submission and navigate the publication processwith ease.
Language (usage and editing services)Please write your text in good American English. Authors who feel their English languagemanuscript may require editing to eliminate possible grammatical or spelling errors and toconform to correct scientific English may wish to use the English Language Editing serviceavailable from Elsevier's WebShop.
Informed consent and patient detailsStudies on patients or volunteers require ethics committee approval and informed consent,which should be documented in the paper. Appropriate consents, permissions and releasesmust be obtained where an author wishes to include patient descriptions, photographs, video,and pedigrees of patients and any other individuals (parents or legal guardians for minors) whocan be identified (including by the patients themselves) in such patient descriptions,photographs, video, and pedigrees. Written consents must be retained by the author but copiesshould not be provided to the journal. Only if specifically requested by the journal in exceptionalcircumstances (for example if a legal issue arises) the author must provide copies of theconsents or evidence that such consents have been obtained. For more information, pleasereview the Elsevier Policy on the Use of Images or Personal Information of Patients or otherIndividuals. Unless you have written permission from the patient (or, where applicable, the nextof kin), the personal details of any patient included in any part of the article and in anysupplementary materials (including all illustrations and videos) must be removed beforesubmission.
Patient Identification
Omitting data or making data less specific to deidentify patients is acceptable, but changingany such data is not acceptable. Only those details essential for understanding and interpretinga specific case report or case series should be provided. Although the degree of specificityneeded will depend on the context of what is being reported, specific ages, race/ethnicity, andother sociodemographic details should be presented only if clinically or scientifically relevantand important. Cropping of photographs to remove identifiable personal features that are notessential to the clinical message may be permitted as long as the photographs are nototherwise altered. Please do not submit masked photographs of patients. Patients' initials orother personal identifiers must not appear in an image.
SubmissionOur online submission system guides you stepwise through the process of entering your articledetails and uploading your files. The system converts your article files to a single PDF file usedin the peer-review process. Editable files (e.g., Word, LaTeX) are required to typeset your article
for final publication. All correspondence, including notification of the Editor's decision andrequests for revision, is sent by e-mail.
Submit your articlePlease submit your article via https://www.editorialmanager.com/repc
RefereesPlease submit the names and institutional e-mail addresses of several potential referees. Formore details, visit our Support site. Note that the editor retains the sole right to decide whetheror not the suggested reviewers are used.
PREPARATION
Peer reviewThis journal operates a rigorous single blind peer review process, in which manuscripts are sentto external reviewers selected from an extensive database. All contributions will be initiallyassessed by the editor for suitability for the journal. Papers deemed suitable are then typicallysent to a minimum of two independent expert reviewers to assess the scientific quality of thepaper. The Editor is responsible for the final decision regarding acceptance or rejection ofarticles. The Editor's decision is final. More information on types of peer review.
Peer reviewers will respond to the Editor within 30 days recommending acceptance, revision orrejection. The Editor will decide within 10 days whether to accept the manuscript withoutmodification, to send the reviewers’ comments to the authors for modification, or to reject it.When modifications are proposed, the authors have 30 days (which can be extended onrequest) to submit a revised version of the manuscript, incorporating the comments of thereviewers and the Editor. Any amendments should be highlighted in a different colour. TheEditor will decide within 10 days whether to accept the new version, reject it, or send it forfurther review by one or more reviewers.
Letters to the Editor and Editorials will be reviewed by the Editorial Board, but external peerreview may also be requested.
Use of word processing softwareIt is important that the file be saved in the native format of the word processor used. The textshould be in single-column format. Keep the layout of the text as simple as possible. Mostformatting codes will be removed and replaced on processing the article. In particular, do notuse the word processor's options to justify text or to hyphenate words. However, do use boldface, italics, subscripts, superscripts etc. When preparing tables, if you are using a table grid,use only one grid for each individual table and not a grid for each row. If no grid is used, usetabs, not spaces, to align columns. The electronic text should be prepared in a way very similarto that of conventional manuscripts (see also the Guide to Publishing with Elsevier). Note thatsource files of figures, tables and text graphics will be required whether or not you embed yourfigures in the text. See also the section on Electronic artwork.To avoid unnecessary errors you are strongly advised to use the 'spell-check' and 'grammar-check' functions of your word processor.
Article structure
SubdivisionDivide your article into clearly defined sections. Each subsection is given a brief heading. Eachheading should appear on its own separate line. Subsections should be used as much aspossible when cross-referencing text: refer to the subsection by heading as opposed to simply'the text'. Use generic names of drugs (first letter: lowercase) whenever possible. Registeredtrade names (first letter: uppercase) should be marked with the superscript registration symbol® or ™ when they are first mentioned.
The Journal recommends the guidelines for publication of the EQUATOR network(http://www.equator-network.org), including the CONSORT statement and its extensions forrandomized trials (http://www.consort-statement.org/), STROBE for observational (cohort, case-control and cross-sectional) studies (http://www.strobe-statement.org/), STARD for diagnosticaccuracy studies (http://www.stard-statement.org/), PRISMA for systematic reviews and meta-analyses (http://www.prisma-statement.org/), SQUIRE for quality improvement studies(http://www.squire-statement.org/) and CARE for case reports (http://www.care-statement.org/).Reporting of the statistical aspects of studies should be in accordance with the StatisticalAna lyses and Methods in the Pub l i shed L i te ra ture (SAMPL) gu ide l ines(http://www.equator-network.org/reporting-guidelines/sampl/).
IntroductionState the objectives of the work and provide an adequate background, avoiding a detailedliterature survey or a summary of the results.
Material and methodsProvide sufficient details to allow the work to be reproduced by an independent researcher.Methods that are already published should be summarized, and indicated by a reference. Ifquoting directly from a previously published method, use quotation marks and also cite thesource. Any modifications to existing methods should also be described.
ResultsResults should be clear and concise.
DiscussionThis should explore the significance of the results of the work, not repeat them. A combinedResults and Discussion section is often appropriate. Avoid extensive citations and discussion ofpublished literature.
ConclusionsThe main conclusions of the study may be presented in a short Conclusions section, which maystand alone or form a subsection of a Discussion or Results and Discussion section.
Cover letter and Essential title page informationSubmission of an article must include a cover letter with the following information:
a brief description of the article’s significance and/or interest;1.a declaration of originality, specifying that none of the paper’s contents have been2.published or are under consideration elsewhere;a declaration that all authors have read and approved the manuscript;3.
a full disclosure of any potential conflict of interest for any of the authors;4.and which manuscript type is being submitted for publication.5.
Title page must contain the following information:
• Title. Concise and informative. Titles are often used in information-retrieval systems. Avoidabbreviations and formulae where possible. Preferably not exceed 12 words. It may also includea subtitle of up to 4 words. All nouns, adjectives and verbs in the title and subtitle must beginwith a capital letter.• Author names and affiliations. Please clearly indicate the given name(s) and familyname(s) of each author and check that all names are accurately spelled. You can add yourname between parentheses in your own script behind the English transliteration. Present theauthors' affiliation addresses (where the actual work was done) below the names. Indicate allaffiliations with a lower-case superscript letter immediately after the author's name and in frontof the appropriate address. Provide the full postal address of each affiliation, including thecountry name and, if available, the e-mail address of each author.• Corresponding author. Clearly indicate who will handle correspondence at all stages ofrefereeing and publication, also post-publication. This responsibility includes answering anyfuture queries about Methodology and Materials. Ensure that the e-mail address is givenand that contact details are kept up to date by the corresponding author.• Present/permanent address. If an author has moved since the work described in the articlewas done, or was visiting at the time, a 'Present address' (or 'Permanent address') may beindicated as a footnote to that author's name. The address at which the author actually did thework must be retained as the main, affiliation address. Superscript Arabic numerals are used forsuch footnotes.• Word count of the manuscript text.
Structured abstractA structured abstract, by means of appropriate headings, should provide the context orbackground for the research and should state its purpose, basic procedures (selection of studysubjects or laboratory animals, observational and analytical methods), main findings (givingspecific effect sizes and their statistical significance, if possible), and principal conclusions. Itshould emphasize new and important aspects of the study or observations.
Abstracts for all article types should not contain any references. Abbreviations should beavoided or kept to a minimum.
The headings will consist of: Introduction and Objectives, Methods, Results and Conclusion(s))
KeywordsImmediately after the abstract, provide the keywords, using British spelling and avoidinggeneral and plural terms and multiple concepts (avoid, for example, 'and', 'of'). Be sparing withabbreviations: only abbreviations firmly established in the field may be eligible. Keywordsshould ideally be selected from the list of MeSH terms available at www.nlm.nih.gov/mesh/.These keywords will be used for indexing purposes.
Abbreviations, Product Names and Gene NamesDo not use abbreviations in the title or abstract and limit their use in the text. Expand allabbreviations at first mention in the text.
Ensure consistency of abbreviations throughout the article.
Do not use abbreviations in the title or abstract and limit their use in the text. Expand allabbreviations at first mention in the text.
Ensure consistency of abbreviations throughout the article.
Names of Drugs, Devices, and Other Products
Use nonproprietary names of drugs, devices, and other products and services, unless thespecific trade name of a drug is essential to the discussion. In such cases, use the trade nameonce and the generic or descriptive name thereafter. Do not include trademark symbols.
Gene Names, Symbols, and Accession Numbers
Authors describing genes or related structures in a manuscript should include the names andofficial symbols provided by the US National Center for Biotechnology Information (NCBI) or theHUGO Gene Nomenclature Committee. Before submission of a research manuscript reporting onlarge genomic data sets (eg, protein or DNA sequences), the data sets should be deposited in apublicly available database, such as NCBI's GenBank, and a complete accession number (andversion number if appropriate) must be provided in the Methods section or Acknowledgment ofthe manuscript.
AcknowledgementsCollate acknowledgements in a separate section at the end of the article before the referencesand do not, therefore, include them on the title page, as a footnote to the title or otherwise. Listhere those individuals who provided help during the research (e.g., providing language help,writing assistance or proof reading the article, etc.)
Units of MeasureLaboratory values are expressed using conventional units of measure, with relevant SystèmeInternational (SI) conversion factors expressed secondarily (in parentheses) only at firstmention. Articles that contain numerous conversion factors may list them together in aparagraph at the end of the Methods section. In tables and figures, a conversion factor to SIshould be presented in the footnote or legend. The metric system is preferred for theexpression of length, area, mass, and volume. For more details, see the Units of Measureconversion table on the website for the AMA Manual of Style.
Artwork
Tables and Figures. Image manipulationRestrict tables and figures to those needed to explain and support the argument of the articleand to report all outcomes identified in the Methods section. Number each table and figure andprovide a descriptive title for each. Every table and figure should have an in-text citation. Verifythat data are consistently reported across text, tables, figures, and supplementary material.
Whilst it is accepted that authors sometimes need to manipulate images for clarity,manipulation for purposes of deception or fraud will be seen as scientific ethical abuse and willbe dealt with accordingly. For graphical images, this journal is applying the following policy: nospecific feature within an image may be enhanced, obscured, moved, removed, or introduced.
Adjustments of brightness, contrast, or color balance are acceptable if and as long as they donot obscure or eliminate any information present in the original. Nonlinear adjustments (e.g.changes to gamma settings) must be disclosed in the figure legend.
Electronic artworkGeneral points• Make sure you use uniform lettering and sizing of your original artwork.• Embed the used fonts if the application provides that option.• Aim to use the following fonts in your illustrations: Arial, Courier, Times New Roman, Symbol,or use fonts that look similar.• Number the illustrations according to their sequence in the text.• Use a logical naming convention for your artwork files.• Provide captions to illustrations separately.• Size the illustrations close to the desired dimensions of the published version.• Submit each illustration as a separate file.A detailed guide on electronic artwork is available.You are urged to visit this site; some excerpts from the detailed information aregiven here.
FormatsIf your electronic artwork is created in a Microsoft Office application (Word, PowerPoint, Excel)then please supply 'as is' in the native document format.Regardless of the application used other than Microsoft Office, when your electronic artwork isfinalized, please 'Save as' or convert the images to one of the following formats (note theresolution requirements for line drawings, halftones, and line/halftone combinations givenbelow):EPS (or PDF): Vector drawings, embed all used fonts.TIFF (or JPEG): Color or grayscale photographs (halftones), keep to a minimum of 300 dpi.TIFF (or JPEG): Bitmapped (pure black & white pixels) line drawings, keep to a minimum of 1000dpi.TIFF (or JPEG): Combinations bitmapped line/half-tone (color or grayscale), keep to a minimumof 500 dpi.Please do not:• Supply files that are optimized for screen use (e.g., GIF, BMP, PICT, WPG); these typically havea low number of pixels and limited set of colors;• Supply files that are too low in resolution;• Submit graphics that are disproportionately large for the content.
Color artworkPlease make sure that artwork files are in an acceptable format (TIFF (or JPEG), EPS (or PDF) orMS Office files) and with the correct resolution. If, together with your accepted article, yousubmit usable color figures then, at no additional charge, these figures will appear in coloronline (e.g., ScienceDirect and other sites) in addition to color reproduction in print. Furtherinformation on the preparation of electronic artwork.
FiguresNumber all figures (graphs, charts, photographs, and illustrations) in the order of their citationin the text. The number of figures should be limited. Avoid complex composite or multipartfigures unless justified.
See Categories of Articles for limits on the number of figures and/or tables according to articletype.
Ensure that each illustration has a caption. Supply captions separately, not attached to thefigure. A caption should comprise a brief title (not on the figure itself) and a description of theillustration. Keep text in the illustrations themselves to a minimum but explain all symbols andabbreviations used written out in full and in alphabetical order. Different panels in a figureshould be identified by capital letters (Figure 1A, Figure 2C, Figure 3A and B, etc. in the text and(A), (B), (C-E), etc. in the captions).
Text graphicsText graphics may be embedded in the text at the appropriate position. See further underElectronic artwork.
TablesInclude a brief title for each table (a descriptive phrase, preferably no longer than 10 to 15words) and number all tables in the order of their citation in the text. Refer to Categories ofArticles for limits on the number of tables.
Do not embed tables as images in the manuscript file or upload tables in image formats, and donot upload tables as separate files. Tables can be placed either next to the relevant text in thearticle, or on separate page(s) at the end.
Place any table notes below the table body. Please avoid using vertical rules and shading intable cells.
All abbreviations used in the table must be written out in full, in alphabetical order, in the tablelegend immediately below the table. Footnotes may be used if necessary, indicated bysuperscript lower-case letters (a, b, c etc.) in the table and in the legend. Asterisks (*, **, *** etc.)may be used to indicate p values only. If a table contains a reference cited in the text, it shouldbe cited with the name of the first author and "et al." followed by the reference number withoutspace (e.g. Millard et al.9).
References
Citation in text. Reproduced material.Please ensure that every reference cited in the text is also present in the reference list (andvice versa). Any references cited in the abstract must be given in full. Unpublished results andpersonal communications are not recommended in the reference list, but may be mentioned inthe text. If these references are included in the reference list they should follow the standardreference style of the journal and should include a substitution of the publication date witheither 'Unpublished results' or 'Personal communication'. Citation of a reference as 'in press'implies that the item has been accepted for publication.
Personal Communications and Unpublished Data
A signed statement of permission should be included from each individual identified as a sourceof information in a personal communication or as a source for unpublished data, and the date ofcommunication and whether the communication was written or oral should be specified.Personal communications should not be included in the list of references but added to the textparenthetically.
Reproduced material
Please verify that all information and materials in the manuscript are original. The journalgenerally does not republish text, tables, figures, or other material from other publishers,except in rare circumstances. If you believe that you must include content that is owned by athird party, please let us know and provide information about all material that has beenpreviously published and, when applicable, include author(s), title of article, title of journal orbook or other publication, and complete citation, doi, and/or URL.
Reference linksIncreased discoverability of research and high quality peer review are ensured by online links tothe sources cited. In order to allow us to create links to abstracting and indexing services, suchas Scopus, CrossRef and PubMed, please ensure that data provided in the references arecorrect. Please note that incorrect surnames, journal/book titles, publication year andpagination may prevent link creation. When copying references, please be careful as they mayalready contain errors. Use of the DOI is highly encouraged.
A DOI is guaranteed never to change, so you can use it as a permanent link to any electronicarticle. An example of a citation using DOI for an article not yet in an issue is: Ribeiro J. Leftventricular noncompaction and Fabry disease: An unlikely association. Rev Port Cardiol.2019. https://doi.org/10.1016/j.repc.2019.12.001. Please note the format of such citationsshould be in the same style as all other references in the paper.
Web referencesAs a minimum, the full URL should be given and the date when the reference was last accessed.Any further information, if known (DOI, author names, dates, reference to a source publication,etc.), should also be given. Web references can be listed separately (e.g., after the referencelist) under a different heading if desired, or can be included in the reference list.
Data referencesThis journal encourages you to cite underlying or relevant datasets in your manuscript by citingthem in your text and including a data reference in your Reference List. Data references shouldinclude the following elements: author name(s), dataset title, data repository, version (whereavailable), year, and global persistent identifier. Add [dataset] immediately before the referenceso we can properly identify it as a data reference. This identifier will not appear in yourpublished article.
References in a special issuePlease ensure that the words 'this issue' are added to any references in the list (and anycitations in the text) to other articles in the same Special Issue.
Reference styleText: Indicate references by superscript numbers in the text. The actual authors can be referredto, but the reference number(s) must always be given.List: Number the references in the list in the order in which they appear in the text.Examples:Reference to a journal publication:17. Reis L, Paiva L, Costa M, Silva J, Teixeira R, Botelho A, et al. Registry of left atrial appendageclosure and initial experience with intracardiac echocardiography. Rev Port Cardiol.
2018;37:763-72. https://doi.org/10.1016/j.repc.2018.03.009.
Reference to a journal publication with an article number:2. Van der Geer J, Hanraads JAJ, Lupton RA. The art of writing a scientific article. Heliyon.2018;19:e00205. https://doi.org/10.1016/j.heliyon.2018.e00205.
Reference to a book:30. Cohn PF. Silent myocardial ischemia and infarction. 3rd ed. New York: Mansel Dekker; 1993.
Reference to a chapter in an edited book:23. Nabel EG, Nabel GJ. Gene therapy for cardiovascular disease. In: Haber E, editor. Molecularcardiovascular medicine. New York: Scientific American;1995.p.79-96.Reference to a website:12. Portuguese Registry on Acute Coronary Syndromes (ProACS). Available at:http://www.clinicaltrials.gov/identifier NCT01642329 [accessed 26 October 2013].Reference to a dataset:[dataset] 5. Oguro M, Imahiro S, Saito S, Nakashizuka T. Mortality data for Japanese oak wiltd isease and surrounding forest composi t ions, Mendeley Data, v1; 2015.https://doi.org/10.17632/xwj98nb39r.1.
Note shortened form for last page number. e.g., 51–9, and that for more than 3 authors the first6 should be listed followed by 'et al.' For further details you are referred to 'UniformRequirements for Manuscripts submitted to Biomedical Journals' (J Am Med Assoc1997;277:927–34)(see also Samples of Formatted References).
Journal abbreviations sourceJournal names should be abbreviated according to the PubMed list.
VideoElsevier accepts video material and animation sequences to support and enhance your scientificresearch. Authors who have video or animation files that they wish to submit with their articleare strongly encouraged to include links to these within the body of the article. This can bedone in the same way as a figure or table by referring to the video or animation content andnoting in the body text where it should be placed. All submitted files should be properly labeledso that they directly relate to the video file's content. In order to ensure that your video oranimation material is directly usable, please provide the file in one of our recommended fileformats with a preferred maximum size of 150 MB per file, 1 GB in total. Video and animationfiles supplied will be published online in the electronic version of your article in Elsevier Webproducts, including ScienceDirect. Please supply 'stills' with your files: you can choose anyframe from the video or animation or make a separate image. These will be used instead ofstandard icons and will personalize the link to your video data. For more detailed instructionsplease visit our video instruction pages. Note: since video and animation cannot be embeddedin the print version of the journal, please provide text for both the electronic and the printversion for the portions of the article that refer to this content.
Supplementary materialSupplementary material such as applications, images and sound clips, can be published withyour article to enhance it. Submitted supplementary items are published exactly as they arereceived (Excel or PowerPoint files will appear as such online). Please submit your material
together with the article and supply a concise, descriptive caption for each supplementary file.If you wish to make changes to supplementary material during any stage of the process, pleasemake sure to provide an updated file. Do not annotate any corrections on a previous version.Please switch off the 'Track Changes' option in Microsoft Office files as these will appear in thepublished version.
RESEARCH DATAThis journal encourages you to share data that supports your research publication in anappropriate data repository, and enables you to interlink the data with your published articles. Ifyou are sharing data, you are encouraged to cite the data in your manuscript and reference list.Please refer to the "References" section for more information about data citation.
Research data refers to the results of observations or experimentation that validate researchfindings. To facilitate reproducibility and data reuse, this journal also encourages you to shareyour software, code, models, algorithms, protocols, methods and other useful materials relatedto the project.
For more information on depositing, sharing and using research data and other relevantresearch materials, visit the research data page.
Mendeley DataThis journal supports Mendeley Data, enabling you to deposit any research data (including rawand processed data, video, code, software, algorithms, protocols, and methods) associated withyour manuscript in a free-to-use, open access repository. Before submitting your article, youcan deposit the relevant datasets to Mendeley Data. Please include the DOI of the depositeddataset(s) in your main manuscript file. The datasets will be listed and directly accessible toreaders next to your published article online.
For more information, visit the Mendeley Data for journals page.
AFTER ACCEPTANCE
ProofsOne set of page proofs (as PDF files) will be sent by e-mail to the corresponding author (if we donot have an e-mail address then paper proofs will be sent by post) or, a link will be provided inthe e-mail so that authors can download the files themselves. Elsevier now provides authorswith PDF proofs which can be annotated; for this you will need to download the free AdobeReader, version 9 (or higher). Instructions on how to annotate PDF files will accompany theproofs (also given online). The exact system requirements are given at the Adobe site.If you do not wish to use the PDF annotations function, you may list the corrections (includingreplies to the Query Form) and return them to Elsevier in an e-mail. Please list your correctionsquoting line number. If, for any reason, this is not possible, then mark the corrections and anyother comments (including replies to the Query Form) on a printout of your proof and scan thepages and return via e-mail. Please use this proof only for checking the typesetting, editing,completeness and correctness of the text, tables and figures. Significant changes to the articleas accepted for publication will only be considered at this stage with permission from the Editor.We will do everything possible to get your article published quickly and accurately. It isimportant to ensure that all corrections are sent back to us in one communication: please checkcarefully before replying, as inclusion of any subsequent corrections cannot be guaranteed.Proofreading is solely your responsibility.
OffprintsThe corresponding author will be notified and receive a link to the published version of the openaccess article on ScienceDirect. This link is in the form of an article DOI link which can beshared via email and social networks. For an extra charge, paper offprints can be ordered viathe offprint order form which is sent once the article is accepted for publication. Bothcorresponding and co-authors may order offprints at any time via Elsevier's Webshop. Authorsrequiring printed copies of multiple articles may use Elsevier Webshop's 'Create Your Own Book'service to collate multiple articles within a single cover.
AFTER PUBLICATIONCorrectionsRequests to publish corrections should be sent to the editorial office. Corrections are reviewedby editors and authors, published promptly, and linked online to the original article.
Postpublication CorrespondenceFor accepted manuscripts, the corresponding author will be asked to respond to letters to theeditor.
AUTHOR INQUIRIESVisit the Elsevier Support Center to find the answers you need. Here you will find everythingfrom Frequently Asked Questions to ways to get in touch.You can also check the status of your submitted article or find out when your accepted articlewill be published.